Case#: V-1; male; age 28; Chinese family

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: V-1 is part of a large consanguineous HCM pedigree. Family segregation information was reported for the MYBPC3 variant. V-1 died suddenly at age 29

CasePresentingHPOs: HP:0001712 HP:0005144 HP:0032092

CaseHPOFreeText: Left ventricular hypertrophy; increased interventricular septal thickness; left ventricular outflow tract obstruction

Genotyping Method: Sanger sequencing and next-generation sequencing

Variant: c.3624delC, missense

ClinVar: 42727

CAID: CA014493

Case1: Male, 12, China

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: parents where not consanguineous, both carried variants.

ParentalTesting: sanger sequencing showed c.1789C>T variant in patients paternal grandmother, and c.3033delG from maternal grandmother

CasePresentingHPOs: HP:0001962 HP:0002094 HP:0001279 HP:0001712 “Palpitations, Dyspnea, Syncope, Left ventricular hypertrophy”

CaseHPOFreeText: symptoms lasted about a year, ECG showed sinus arrhythmia, high left ventricle voltage

CaseNotHPOs: “the patient had no skeletal muscle disease or mental retardation. The diagnosis of glycogen storage disease was also excluded.”

CaseNotHPOFreeText: no other family members diagnosed with heart disease

CasePreviousTesting: diagnosed 3 months before presentation with HCM, no prior genetic testing, but there was echocardiogram and ecg testing.

Genotyping Method: Sanger and NGS

FunctionalAnalysis: no functional analysis preformed

Variant: c.1789C>T (p.Arg597Trp), c.3033delG (p.Gln1012Serfs*8)

ClinVar: NM_000256.3(MYBPC3):c.1789C>T (p.Arg597Trp),

CAID: no results

gnomAD: no results

AdditionalInfo: treated with metoprolol, at 3 moth follow up lvot decreased

PMID: 30896616

Gene: MYBPC3

HGNC ID: HGNC:7551

Case#: cohort annotation with 8 probands and 25 relatives that are carriers.

DiseaseAssertion: Pathogenic MYBPC3 c.2149–1G>A variant associated with hypertrophic cardiomyopathy

FamilyInfo: Eight unrelated probands, all male, with 45 relatives, 25 where carriers of the variant, 12 had HCM and 13 where unaffected

ParentalTesting: not reported

CasePresentingHPOs: HP:0001712 HP:0002094 HP:0001279 HP:0100749 HP:0001962 HP:0001649 “Left ventricular hypertrophy, Dyspnea, syncope, Chest pain, Palpitations, Tachycardia CaseHPOFreeText:HCM with variable expression with men diagnosed younger then women

CaseNotHPOs:not reported

CaseNotHPOFreeText: not reported

CasePreviousTesting: not reported

Genotyping Method: Sanger sequencing

FunctionalAnalysis: rna analysis shows abnormal transcript, suggesting founder effect.

Variant: MYBPC3 NM_000256.3:c.2149–1G>A

ClinVar: 177814

CAID: not reported

gnomAD:not reported

AdditionalInfo: HCM penetrance increased with age and was highest in males over 30

Case#: 28 patients, 21 retrospectives, 7 prospectives.

DiseaseAssertion: patients had reported unsolved metabolic condition, possible mitochondrial disorder. Onset ranged from prenatal to 7 years, study ranged from 1 year to 29, 9 patients died

FamilyInfo:individual family histories not summerized

ParentalTesting:all reported varients confirmed via sanger sequencing on parents, though most had proband only sequencing.

CasePresentingHPOs: “motor developmental delay, intellectual disability, developmental regression, muscle weakness, dystonia, choreoathetosis, ataxia, tremor, nystagmus, strabismus, Epilepsy, Brain atrophy CaseHPOFreeText: mri showed brain atrophy in 10, white matter injury in 6, hypo/aplasia of the corpus collosum in 3, mitochondrial hypoplasia in 5, myofibular disorganization in 2.

CaseNotHPOs: not reported

CaseNotHPOFreeText: not reported

CasePreviousTesting: retrospective patients had mtdna investigations done without diagnosis

Genotyping Method: WES and Sanger

FunctionalAnalysis: reported for selected finding such as impaired adp/atp transports for a variant slc25a4, no cohort wide analysis

Variant: heterogenous findings across the cohort genes read included SLC25A4, POLG, SPATA5, NDUFB11, SMN1, MYH2, LMNA, TSPOAP1, CACNA1A, ALS2, SCN2A, EPG5, NKX1-2, ATRX, ABCC6, and MYBPC3. Though for the cardiomyopathy purposes, c.1828G > A, p.(Asp610Asn) c.1543_1545delAAC, p.(Asn515del)

ClinVar: 2247822

CAID: not reported

gnomAD: not reported

AdditionalInfo: WES diagnostic yield was 16/28, 4 patients where diagnosed via MD. The paper suggests WES as a first step for children though there where sensitivity limitations.

Case#:1 Male, 27, no reported ethnicity

DiseaseAssertion: sinus tachycardia, signs of hypertrophy of both atria and ventricles

FamilyInfo: proband had a sister who died at 15 days of age due to a congenital heart disease (transposition of the great arteries). No other relative was diagnosed with cardiomyopathy of other cardiac disease before 50 years of age

ParentalTesting: family history was unremarkable. Parents were not consanguineous.

CasePresentingHPOs: HP:0001639, HP:0001644, HP:0200128, HP:0004308 "Hypertrophic cardiomyopathy, Dilated cardiomyopathy, Biventricular hypertrophy, Ventricular arrhythmia <br /> CaseHPOFreeText: Dilated cardiomyopathy recorded at age of 4, Severe respiratory infection led to circulatory decompensation and acute femoral thrombosis"

CaseNotHPOs: none reported

CaseNotHPOFreeText: no evidence of myeloproliferative disease was found when bone marrow trepanobiopsy was preformed.

CasePreviousTesting: dcm diagnosis at age 4, Whole exome sequencing (WES)

Genotyping Method: WES, NGS, & Sanger

FunctionalAnalysis: none reported

Variant: chr11:g.47357432_47357458del, ENST00000545968.1: c.2711_2737del, p.2711_2737del

ClinVar: VCV000978729.2

gnomAD: ENSG00000134571.12

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Case1: 38, Male

FamilyInfo: ”identification of nine additional heterozygous carriers of the p.V79I mutation, none of whom fulfilled the diagnostic criteria for HCM” Pedigree in Figure 1, and Table 1 gives identifiers in variant carriers.

CasePresentingHPOs:HP:0030148

CaseHPOFreeText: “Echocardiography demonstrated asymmetrical septal ventricular hypertrophy…and left atrial dilation”

CaseNotHPOs:HP:0001279, HP:0000822

CaseNotHPOFreeText: ”He was asymptomatic and had never experienced cardiac symptoms, systemic hypertension, or syncope.”

Genotyping Method:Genotyping of 11 sarcomere genes

Variant:(c.235G > A), p.V79I

ClinVar:CA013672

Case1: 35, Female, Caucasian

DiseaseAssertion: Patient was asymptomatic

FamilyInfo: “ significant family history of hypertrophic cardiomyopathy (HCM), including sudden cardiac death of unknown cause in one son and HCM in two other children”

CaseHPOFreeText: “extensive, diffuse, poorly demarcated LGE throughout the LV ventricle”

CaseNotHPOFreeText: “CMR showed normal left ventricular (LV) systolic function…and normal wall thickness ”

CasePreviousTesting:

Genotyping Method: Subsequent genotyping

Variant: c.305G>A (p.Arg102Gln)

ClinVar:CA004273

Case1: 8 year old female

DiseaseAssertion: Heart failure

FamilyInfo: “ no family history of sudden cardiac death or cardiomyopathy” Pedigree in Figure 5.

ParentalTesting: Variant not found in parents

CasePresentingHPOs:HP:0010741, HP:0001723

CaseHPOFreeText: “biatrial enlargement of ST-segment depression in the inferior and lateral precordial leads” “Echocardiography revealed the enlargement of both atria…slight pericardial effusion, and a LV ejection fraction of 55%”

CaseNotHPOFreeText: “LV global longitudinal strain measured by speckle-tracking echocardiography was normal” “Late gadolinium enhancement was negative.” “no evidence of pulmonary embolism, anomalous pulmonary venous drainage, or pulmonary arteriovenous fistulas” “The following laboratory findings were normal: thyroid function, liver chemistry tests, rheumatic disease antibody levels, troponin I, creatinine, and blood urea nitrogen levels, white blood cell count, urine analysis, D-dimer levels, hepatitis panel screening, and serum free light chain concentrations; HIV antibody levels were negative.”

Genotyping Method: Next generation sequencing

Variant: c.574C > T p.R192C)

ClinVar:CA021951

Case1: Female, 53

DiseaseAssertion: Restrictive Cardiomyopathy

FamilyInfo:Pedigree in Fig 1. shows “ The proband (II.11) has five siblings and three nieces with cardiomyopathy,” “the proband’s two oldest siblings were diagnosed with idiopathic DCM”

CasePresentingHPOs: HP:0002094, HP:0001962, HP:0031329, HP:0001688, HP:0001709

CaseHPOFreeText:”Echocardiography revealed massive biatrial enlargement (Fig. 2a) and markedly abnormal diastolic function” “she had mild hypertrophy localized to the mid-septum” “progressive atrial enlargement”

CaseNotHPOs:HP:0012436,

CaseNotHPOFreeText: “with no systolic anterior motion of the anterior mitral valve leaflet or left ventricular outflow tract obstruction” “The sample was negative for eosinophilic infiltrate, myocarditis, sarcoidosis, amyloidosis and hemochromatosis.”

CasePreviousTesting: Sequenced TNNT2, TTN, MYL3, MYBPC, MYL2, MYH7, ACTC1, TPM1, and TNNI3

Genotyping Method: PCR

Variant: c.266T>A (p.Ile89Asn)

ClinVar:CA004157

gnomAD: To be found

AdditionalInfo: Autosomal Dominant trait, heterozygous missense mutation in TNNT2

Case1: 21, Male

DiseaseAssertion: To be found

FamilyInfo: No remarkable family history.

CasePresentingHPOs: HP:0003401, HP:0410173, HP:0001688

CaseHPOFreeText: "arietal ischemic lesions, elevated high-sensitivity I troponin, left ventricle (LV) dilation, apical hypokinesia, apical thrombus, and multifocal nonischemic late gadolinium enhancement with edema" " elevated N-terminal pro–B-type natriuretic peptide and low c-reactive protein"

CaseNotHPOs: HP:0001297, HP:0012819

CaseNotHPOFreeText: "A cardioembolic stroke due to myocarditis with an LV thrombus was assumed" “Ischemic heart disease was considered unlikely at presentation” “Cardiac sarcoidosis was considered but was not supported” “Autoimmune myocarditis and other systemic inflammatory causes were also considered” “Giant cell myocarditis was considered to be unlikely”

CasePreviousTesting:

Genotyping Method: Whole genome sequencing

Variant: c.1484G>A; p.Arg495Gln

ClinVar: CA010464

gnomAD: To be found

Case#: Jiang_2015_Family_087_Patient_III:2, male, age 28 at time of report, national origin listed as Chinese

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0025573 (Mild myopia), HP:0032037 (Mildly reduced visual acuity), HP:0007703 (Abnormality of retinal pigmentation), HP:0008275 (Abnormal light-adapted electroretinogram), HP:0000642 (Red-green dyschromatopsia)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000662 (Nyctalopia), HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing included mapping the disease locus in this family to the region of chr17p13.1-2 containing AIPL1, PITPNM3, and GUCY2D (PMID: 23734073).

CaseMethod1: Sanger sequencing of PCR products from all exons and flanking regions of the GUCY2D, AIPL1, and PITPNM3 loci.

CaseMethod2: Allele-specific PCR analysis to genotype the proband and family members

CaseGenotypingMethod: The proband was genotyped by linkage mapping of the phenotype within affected and unaffected members of his family, followed by Sanger sequencing of PCR products from all exons and flanking regions of the 3 candidate loci, and finally allele-specific PCR analysis to genotype the proband and family members.

Variant: The proband harbors the NM_000180.4(GUCY2D)):c.2545A>G (p.Thr849Ala) variant in the heterozygous state.

CAID: CA397953755

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.4(GUCY2D)):c.2545A>G (p.Thr849Ala) is a missense variant located within the coiled-coil domain that mediates dimerization. Missense variants at the nearby Codon 838 have proven to constitute a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565). Cases from this family appear to be less severely affected than those.

CaseAddInfo: The proband has two older family members who are similarly affected and who harbor the variant.

CasePMIDs: PMID: 23734073

Case#: Jiang_2015_Patient_010043, female, age 28 at time of report, national origin listed as Chinese

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0011003 (High myopia), HP:0007663 (Reduced visual acuity), HP:0007703 (Abnormality of retinal pigmentation), HP:0030329 (Retinal thinning), HP:0008275 (Abnormal light-adapted electroretinogram)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000662 (Nyctalopia), HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing appears to have been limited to clinical phenotyping.

CaseMethod1: Sanger sequencing of PCR products from all exons and flanking regions of the GUCY2D locus

CaseMethod2: HhaI restriction digest of the PCR-amplified exon 13

CaseGenotypingMethod: The proband was genotyped by Sanger sequencing of PCR products from all exons and flanking regions of the GUCY2D locus. Parents were implied to have been genotyped as well. The patient and family members were subjected to additional genotyping through restriction fragment length polymorphism analysis, then confirmation by HhaI restriction endonuclease digestion of PCR products from the relevant exon 13.

Variant: The proband harbors the NM_000180.4(GUCY2D):c.2513G>A (p.Arg838His) variant in the heterozygous state.

ClinVar: 9357

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.4(GUCY2D):c.2513G>A (p.Arg838His) is a missense variant located within the coiled-coil domain that mediates dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565). The variant has been reported in an apparently unrelated family from this same publication. The p.Arg838His substitution has been shown to disrupt the calcium sensitivity of GUCY2D and to trigger the inability to inactivate cyclase activity at high physiological calcium ion concentrations (PMID: 11115851).

CaseAddInfo: The proband's parents are unaffected and negative for the variant, indicating that this may be a de novo case. It is uncertain whether genotyping methods were sufficient to confirm paternity and maternity.

CasePMIDs: N/A

Case#: Jiang_2015_Family_010153_Patient_III:1, female, age 37 at time of report, national origin listed as Chinese

CasePresentingHPOs: HP:0003621 (Juvenile onset), HP:0007663 (Reduced visual acuity), HP:0000639 (Nystagmus), HP:0030329 (Retinal thinning), HP:0011516 (Achromatopsia), HP:0030465 (Undetectable light-adapted electroretinogram), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0007703 (Abnormality of retinal pigmentation)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000662 (Nyctalopia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing appears to have been limited to clinical phenotyping.

CaseMethod1: Sanger sequencing of PCR products from all exons and flanking regions of the GUCY2D locus

CaseMethod2: HhaI restriction digest of the PCR-amplified exon 13

CaseGenotypingMethod: The proband and her family members were subjected to additional genotyping through restriction fragment length polymorphism analysis, then confirmation by HhaI restriction endonuclease digestion of PCR products from the relevant exon 13.

Variant: The proband harbors the NM_000180.4(GUCY2D):c.2513G>C (p.Arg838Pro) variant in the heterozygous state.

ClinVar: 811743

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.4(GUCY2D):c.2513G>C (p.Arg838Pro) is a missense variant located within the coiled-coil domain that mediates dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565).

CaseAddInfo: The proband is a member of a family with several other affected family members who carry the variant.

CasePMIDs: N/A

Case#: Mykykyn_2002_Proband_PR1-1, gender not specified, age not described, family origin reported as from Puerto Rico

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been previously diagnosed with Bardet-Biedl syndrome based on at least three of the following features; obesity, polydactyly, renal anomalies, retinopathy, hypogonadism, and/or mental retardation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and their affected and unaffected family members were subjected to mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers.

CaseMethod1: linkage mapping

CaseMethod2: Sanger sequencing of BBS1

CaseGenotypingMethod: The proband and their affected and unaffected family members were subjected to linkage mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers. Sanger sequencing of BBS1 was subsequently used to identify the variant.

Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant in the homozygous state.

ClinVar ID: 12143

gnomAD: The variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1

VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant.

CaseAddInfo: The proband's family is described as consanguineous.

CasePMIDs: N/A

Case#: Moore_2006_Family_1_Patient_II-1, male, 15 years old at time of report, national origin not mentioned

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0011109 (Chronic sinusitis), HP:0031353 (Otitis media with effusion), HP:0002837 (Recurrent bronchitis), HP:0100750 (Atelectasis), HP:0002110 (Bronchiectasis), HP:0006536 (Airway obstruction), HP:0005101 (High-frequency hearing impairment), HP:0012263 (Immotile cilia), HP:0012258 (Abnormal axonemal organization of respiratory motile cilia), HP:0012264 (Absent central microtubular pair morphology of respiratory motile cilia), HP:0012256 (Absent outer dynein arms), HP:0012257 (Absent inner dynein arms)

CaseHPOFreeText: The patient received a diagnosis of primary ciliary dyskinesia in early childhood, followed by retinitis pigmentosa diagnosed later in childhood. Atelectasis was severe and led to partial lobectomy at age 14 years. Microbiology detected Haemophilus influenzae. Biopsies showed both motile and immotile cilia.

CaseNotHPOs: HP:0002643 (Neonatal respiratory distress), HP:0012418 (Hypoxemia), HP:0030853 (Heterotaxy)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Based on a family history consistent with X-linked inheritance, the patient and family members were subjected to segregation analysis using 4 microsatellite markers on the X chromosome. Genome-wide methods were not used for genotyping.

CaseMethod1: Sanger sequencing of PCR products from each of the 19 coding exons of RPGR, including the flanking intronic sequences

CaseMethod2: N/A

CaseGenotypingMethod: The patient and family members were subjected to segregation analysis using 4 microsatellite markers on the X chromosome. Sanger sequencing of PCR products from each of the 19 coding exons of RPGR, including the flanking intronic sequences, was then performed. Genome-wide methods were not used for genotyping.

Variant: The patient harbors the NM_001034853.2(RPGR):c.572_619+9del variant in the hemizygous state.

CAID: CA2573131867

gnomAD: This variant was not found in gnomAD v.2.1.1.

VariantEvidence: NM_001034853.2(RPGR):c.572_619+9del is a deletion variant spanning the function between exon 6 and intron 6. It has been shown to yield a shorter mRNA generated by the use of a cryptic splice donor site in exon 6 (Figure 4) that is predicted to trigger a frameshift and nonsense-mediated decay or disruption of the C-terminal 84% of the protein product.

CaseAddInfo: The proband is a member of Family 1, which has a pedigree shown in Figure 1. The patient's family includes a similarly affected brother and a mother diagnosed with retinitis pigmentosa, both harboring the RPGR variant of interest. Parents are reportedly non-consanguineous.

CasePMIDs: N/A

Case#: Pusch_2000_Family_9069_proband, male, 18 years of age, Swedish family origin

CasePresentingHPOs: HP:0007642 (Congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)

CaseHPOFreeText: ERG with absent oscillatory-potential wavelets

CaseNotHPOs: HP:0001098 (Abnormal fundus morphology), HP:0030473 (Abnormal light-adapted flicker electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Linkage analysis and haplotype analysis were performed using RFLP X-chromosomal markers and SSCP.

CaseMethod1: Sanger sequencing of PCR amplified exons from NYX

CaseMethod2: N/A

CaseGenotypingMethod: Linkage analysis and haplotype analysis were performed using RFLP X-chromosomal markers and SSCP. This was followed by Sanger sequencing of PCR products to identify the variant.

Variant: The proband harbors the NM_022567.2(NYX):c.559_560delinsAA (p.Ala187Lys) variant in his X-chromosome.

ClinVar: 11423

gnomAD: NM_022567.2(NYX):c.559_560delinsAA (p.Ala187Lys) was not found in gnomAD.

VariantEvidence: This is missense variant does not have experimental evidence of impact on the protein product, but is a recurrent variant observed in this paper in multiple Swedish families (2996, 9069, and 2999) with a shared haplotype.

CaseAddInfo: Phenotype information is found in PMID: 12397430.

CasePMIDs: 12397430

Case#: Pusch_2000_Family_2438B_proband, male, 36 years of age, origin not mentioned (PMID: 12397430)

CasePresentingHPOs: HP:0007642 (Congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)

CaseHPOFreeText: ERG with absent oscillatory-potential wavelets

CaseNotHPOs: HP:0001098 (Abnormal fundus morphology), HP:0030473 (Abnormal light-adapted flicker electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Linkage analysis and haplotype analysis were performed using RFLP X-chromosomal markers and SSCP.

CaseMethod1: Sanger sequencing of PCR amplified exons from NYX

CaseMethod2: N/A

CaseGenotypingMethod: Linkage analysis and haplotype analysis were performed using RFLP X-chromosomal markers and SSCP. This was followed by Sanger sequencing of PCR products to identify the variant.

Variant: The proband harbors the NM_001378477.3(NYX):c.77G>C (p.Cys26Ser) variant in his X-chromosome.

ClinVar: 99843

gnomAD: NM_001378477.3(NYX):c.77G>C (p.Cys26Ser) was not found in gnomAD.

VariantEvidence: This is missense variant does not have experimental evidence of impact on the protein product, but is a recurrent variant observed in multiple apparently unrelated families (2438B, 5886, and 5884) from this paper.

CaseAddInfo: Phenotype information is found in PMID: 12397430.

CasePMIDs: 12397430

Case#: Pusch_2000_Familly_9606_Proband, male, age and race not mentioned

CasePresentingHPOs: HP:0030640 (Complete congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)

CaseHPOFreeText: ERG with absent oscillatory-potential wavelets

CaseNotHPOs: HP:0001098 (Abnormal fundus morphology), HP:0030473 (Abnormal light-adapted flicker electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing of PCR amplified exons from NYX

CaseMethod2: N/A

CaseGenotypingMethod: The proband and family members were subjected to Sanger sequencing of NYX to identify the variant.

Variant: The proband harbors the NM_001378477.3(NYX):c.90C>A (p.Cys30Ter) variant on the X chromosome.

ClinVar: 11422

gnomAD: NM_001378477.3(NYX):c.90C>A (p.Cys30Ter) was not found in gnomAD.

VariantEvidence: This nonsense variant is located in exon 2/3 and is predicted to trigger NMD. It introduces a premature stop codon that would truncate 93% of the protein product.

CaseAddInfo: This variant appears not only in Family 9606, but also in Family 2438T, yet is not suspected to be a founder alelle.

CasePMIDs: N/A

Case#: Peng_2009_Patient_IV:3, male, age of onset not reported, family origin reported to be from China

CasePresentingHPOs: HP:0006934 (Congenital nystagmus)

CaseHPOFreeText: The proband has been diagnosed with congenital nystagmus, with family members showing an X-linked pattern of inheritance.

CaseNotHPOs: N/A

CaseNotHPOFreeText: The affected individuals are described as lacking the typical signs of ocular albinism 1, but details have not been described.

CasePreviousTesting: Genotyping was initially performed by linkage mapping using markers on the X chromosome.

CaseMethod1: linkage analysis

CaseMethod2: Sanger sequencing

CaseGenotypingMethod: Genotyping was initially performed by linkage mapping using markers on the X chromosome, followed by Sanger sequencing of PCR products from each exon of the GPR143 gene. Family members were subsequently genotyped by allele-specific PCR.

Variant: The proband harbors the NM_000273.3:c.291_309dup (p.Asp104PhefsTer3) variant in the hemizygous state.

CAID: CA2573320693

gnomAD: This variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_000273.3:c.291_309dup (p.Asp104PhefsTer3) is a frameshift variant in exon 2 of 9, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 75% of the protein product.

CaseAddInfo: The proband is from a family with at least three other affected males who also harbor the variant.

CasePMIDs: N/A

Case#: Xin_Patient_4, sex not mentioned, age 12 at time of study, U.S. nationality, ethnicity listed as Hispanic

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient is believed to be homozygous for the NM_006493.4(CLN5):c.936del (p.Phe312LeufsTer4) variant as well as the NM_006493.4(CLN5):c.956A>G (p.Lys319Arg) variant (considered likely benign). The proband is also apparently homozygous for two non-coding variants (an intron 1 variant referred to as "Int1, c.320+8C>T" and a 3'UTR variant referred to as "3'UTR c.1224+33A>G").

ClinVar: 56528 and 128778 (in cis, homozygous)

gnomAD: Maximum allele frequency for the NM_006493.4(CLN5):c.936del (p.Phe312LeufsTer4) variant is 0.0001159 (Latino / Admixed American population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77574958-AT-A Maximum allele frequency for NM_006493.4(CLN5):c.956A>G (p.Lys319Arg) is 0.4186 (in the African / African-American population, 2136 homozygotes). https://gnomad.broadinstitute.org/variant/13-77574983-A-G

VariantEvidence: NM_006493.4(CLN5):c.936del (p.Phe312LeufsTer4) is a frameshift variant predicted to disrupt ~13% of the protein product. The C-terminal region disrupted has been shown to be glycosylated and is important for proper localization of the protein (PMID:19309691).

CaseAddInfo: Parents are not available for genotyping, so homozygosity of variants is assumed. This conclusion was supported by failure to detect a deletion.

CasePMIDs: N/A

Case#: Xin_Patient_8, sex not mentioned, age 5.5 at onset, U.S. nationality, Indian ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000512 (Abnormal electroretinogram), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset)

CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 5.5). Cognitive regression (age 6), and visual findings (abnormal ERG) had later onset.

CaseNotHPOs: HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)

CaseNotHPOFreeText: The electron microscopy findings referred to above (from conjunctiva biopsy) were normal.

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient is believed to be homozygous for the NM_006493.4(CLN5):c.428A>G p.Asn143Ser variant.

ClinVar: 56539 (homozygous)

gnomAD: The NM_006493.4(CLN5):c.428A>G p.Asn143Ser variant is absent from gnomAD.

VariantEvidence: NM_006493.4(CLN5):c.428A>G p.Asn143Ser is a missense variant at a highly conserved residue, and is speculated by the authors to function as an exonic splicing enhancer. SpliceAI finds some evidence of a possible donor loss (change score of 0.02) or acceptor gain (change score of 0.09).

CaseAddInfo: Parents have not been subjected to genotyping, so homozygosity of variants is assumed. This conclusion was supported by failure to detect a deletion. Family history of non-consanguinity or consanguinity was not mentioned, but both parents share the same local area of origin within India.

CasePMIDs: N/A

Case#: Xin_Patient_10, sex not mentioned, age 5 at onset, U.S. nationality, Pakistani ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 5). Cognitive regression and Seizures had onset at age 5, while Visual loss had onset at age 24.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient is believed to be homozygous for the NM_006493.4(CLN5):c.379dup p.Thr127AsnfsTer11 variant.

CAID: CA611398060 (homozygous)

gnomAD: The maximum allele frequency for the NM_006493.4(CLN5):c.379dup p.Thr127AsnfsTer11 variant is 0.00003266 (jn the South Asian population, with no homozygotes).

VariantEvidence: NM_006493.4(CLN5):c.379dup p.Thr127AsnfsTer11 is a frameshift variant that disrupts ~65% of the protein product and is likely to trigger nonsense mediated decay.

CaseAddInfo: Parents have not been subjected to genotyping, so homozygosity of variants is assumed. This conclusion was supported by failure to detect a deletion, and by family history of consanguinity.

CasePMIDs: N/A

Case#: Allen_2003_Familly_X08_Proband, male, age not mentioned, British national origin

CasePresentingHPOs: HP:0007642 (Congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)

CaseHPOFreeText: ERG with absent scotopic oscillatory potential, subnormal ON response

CaseNotHPOs: N/A

CaseNotHPOFreeText: Normal OFF response

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing of PCR-amplified exons from NYX and CACNA1F

CaseMethod2: Haplotype analysis using microsatellite markers surrounding the NYX locus

CaseGenotypingMethod: The proband and family members were subjected to Sanger sequencing of NYX to identify the variant, followed by microsatellite-based haplotype analysis of families sharing the same variant.

Variant: The proband harbors the NM_022567.2(NYX):c.895C>T (p.Gln299Ter) variant on the X chromosome.

CAID: CA412991558

gnomAD: NM_022567.2(NYX):c.895C>T (p.Gln299Ter) was not found in gnomAD.

VariantEvidence: NM_022567.2(NYX):c.895C>T (p.Gln299Ter) is a nonsense variant in exon 3/3 that is not predicted to trigger NMD but truncates the C-terminal 38% of the protein product. A separate publication (PMID: 14507859) indicates that variants (such as this one) that remove the C-terminal GPI anchor disrupt NYX function by triggering its mislocalization to and accumulation in the ER and Golgi and its absence from its normal destination at the cell surface.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Allen_2003_Familly_X05_Proband, male, age not mentioned, British national origin

CasePresentingHPOs: HP:0007642 (Congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)

CaseHPOFreeText: ERG with absent scotopic oscillatory potential, subnormal ON response

CaseNotHPOs: N/A

CaseNotHPOFreeText: Normal OFF response

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing of PCR-amplified exons from NYX and CACNA1F

CaseMethod2: Haplotype analysis using microsatellite markers surrounding the NYX locus

CaseGenotypingMethod: The proband and family members were subjected to Sanger sequencing of NYX to identify the variant, followed by microsatellite-based haplotype analysis of families sharing the same variant.

Variant: The proband harbors the NM_022567.2(NYX):c.1122_*11del (p.Ser374ArgfsTer10) variant on the X chromosome.

CAID: CA2573050969

gnomAD: NM_022567.2(NYX):c.1122_*11del (p.Ser374ArgfsTer10) was not found in gnomAD.

VariantEvidence: NM_022567.2(NYX):c.1122_*11del (p.Ser374ArgfsTer10) is a frameshift variant in exon 3/3 that is not predicted to trigger NMD but disrupts the C-terminal 22% of the protein product. A separate publication (PMID: 14507859) indicates that variants (such as this one) that remove the C-terminal GPI anchor disrupt NYX function by triggering its mislocalization to and accumulation in the ER and Golgi and its absence from its normal destination at the cell surface. This is a recurrent variant reported here in multiple apparently unrelated British families (X05 and X09).

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Khan_2016_Proband_2, male, age 4 months at time of referral, national origin indicated as Saudi

CasePresentingHPOs: Abnormal visual fixation HP:0025404, Nystagmus HP:0000639, Infantile onset HP:0003593, Visual impairment HP:0000505, Deeply set eye HP:0000490, Esotropia HP:0000565, High hypermetropia HP:0008499, Undetectable electroretinogram HP:0000550,

CaseHPOFreeText: The proband has been diagnosed with Leber congenital amaurosis, with poor visual fixation and nystagmus as the presenting features. Staring at lights was a phenotype.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband consisted of a 44-gene next generation sequencing-based panel for retinal dystrophy showing no other potential cause of retinal features.

CaseMethod1: next-generation sequencing panel (44 genes)

CaseMethod2: Sanger sequencing of PRPH2

CaseGenotypingMethod: Previous testing in the proband consisted of a 44-gene next generation sequencing-based panel for retinal dystrophy showing no other potential cause of retinal features. The presence of the variant was confirmed by Sanger sequencing of PRPH2.

Variant: The proband harbors the NM_000322.5(PRPH2):c.136C>T (p.Arg46Ter) variant in the homozygous state.

ClinVar ID: 13179

gnomAD: The NM_000322.5(PRPH2):c.136C>T (p.Arg46Ter) variant is found in gnomAD v4.0.0 at a frequency of 0.00004005 (3 alleles / 74906 total alleles, with 0 homozygotes) in the African / African-American population https://gnomad.broadinstitute.org/variant/6-42722199-G-A?dataset=gnomad_r4

VariantEvidence: NM_000322.5(PRPH2):c.136C>T (p.Arg46Ter) is a nonsense variant in exon 1 of 3 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal 87% of the protein product.

CaseAddInfo: The proband is the child of first cousin parents who appeared sub-clinically affected but were not genotyped. A second, similarly affected sibling shares the same genotype.

CasePMIDs: N/A

GroupName: Tabata_1998_Group

GroupPresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0025094 (Disciform macular scar)

GroupHPOFreeText: Relatively late onset of phenotypes during the 6th, 7th, or 8th decade of life.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupDemographics

NumberMales: 4

NumberFemales: 5

CountryOrigin: Japan

Ethnicity: Not mentioned

Race: Not mentioned

AgeRange: The individuals mentioned range in age from 52 to 75.

TotalNumber: 9

FamilyInfo: 9

NoFamily: 0

VariantCount: 5

NonVariant: 4

OtherVariant: N/A

GroupPreviousTesting: Sanger sequencing of PCR-amplified exon 5

GroupGenotypingMethod: PCR-based heteroduplex analysis using gel electophoresis, as well as SSCP analysis of exon 5.

FamilyLabel: Tabata_1998_Family_Ch

Family#PresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0025094 (Disciform macular scar), HP:0000529 (Progressive visual loss)

FamilyHPOFreeText: Onset of decreased central vision was seen in the 6th or 7th decade of life (between the ages of 52 and 66), although abnormal findings on ophthalmoscopy (early macular degeneration) found in 4th decade of life.

FamilyNotHPOs: HP:0007994 (Peripheral visual field loss)

FamilyNotHPOFreeText: Although central vision was progressively lost, peripheral fundi remained uninvolved and affected individuals continued to walk unguided into the 8th decade of life and beyond.

CountryOrigin: Japan

Family#PreviousTesting: PCR-based heteroduplex analysis using gel electophoresis

Family#GenotypingMethod: Sanger sequencing

Affected: 2

Unaffected: 3

Segregations: N/A

PublishedLOD: N/A

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Tabata_1998_Family_Ch_patient_1

Variant: NM_000362.5:c.439-2dup (TIMP3) is predicted to disrupt a splice acceptor site at the junction of intron 4 and exon 5.

CAID: CA1139771334

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: While Family Ue and Family Ch are two distinct families, united by the NM_000362.5:c.439-2dup (TIMP3) variant harbored by their affected family members, they share a geographical place of origin within Japan (PMID:9760202).

FamilyPMIDs: N/A

Case: Tabata_1998_Family_Ue_patient_1, female, 73 years of age at onset of visual symptoms, country of origin Japan

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: The proband has two affected siblings. All three were subjected to genotyping.

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0025094 (Disciform macular scar), HP:0000603 (Central scotoma), HP:0030496 (Macular exudate), HP:0030506 (Yellow/white lesions of the retina), HP:0025243 (Subretinal hemorrhage), HP:0000580 (Pigmentary retinopathy), HP:0030491(Choriocapillaris atrophy)

CaseHPOFreeText: Onset of decreased central vision was seen in the 8th decade of life (both eyes between the ages of 73 and 77).

CaseNOTHPOs: HP:0007994 (Peripheral visual field loss), HP:0000512 (Abnormal electroretinogram), HP:0000662 (Nyctalopia)

CaseNOTHPOFreeText: Although central vision was decreased, peripheral fundi remained uninvolved. Patient had no difficulties with daily activities.

CasePreviousTesting: PCR-based heteroduplex analysis using gel electophoresis

CaseGenotypingMethod: Sanger sequencing

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: NM_000362.5:c.439-2dup (TIMP3) is predicted to disrupt a splice acceptor site at the junction of intron 4 and exon 5.

CAID: CA1139771334

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant introduces an extra base within a splice acceptor site within intron 4, two bases upstream of exon 5.

Case: Tabata_1998_Family_Ch_patient_1, male, 52 years of age at onset of visual symptoms, country of origin Japan

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: The proband passed on the variant to his son and likely inherited it from his affected mother (who was not genotyped).

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0025094 (Disciform macular scar), HP:0000529 (Progressive visual loss), HP:0000603 (Central scotoma)

CaseHPOFreeText: Onset of decreased central vision was seen in the 6th decade of life (both eyes between the ages of 52 and 57).

CaseNOTHPOs: HP:0007994 (Peripheral visual field loss), HP:0000512 (Abnormal electroretinogram)

CaseNOTHPOFreeText: Although central vision was progressively lost, peripheral fundi have remained uninvolved and the individual has continued to walk unguided into the 8th decade of his life.

CasePreviousTesting: PCR-based heteroduplex analysis using gel electophoresis

CaseGenotypingMethod: Sanger sequencing

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: NM_000362.5:c.439-2dup (TIMP3) is predicted to disrupt a splice acceptor site at the junction of intron 4 and exon 5.

CAID: CA1139771334

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant introduces an extra base within a splice acceptor site within intron 4, two bases upstream of exon 5.

FamilyLabel: Tabata_1998_Family_Ue

Family#PresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0025094 (Disciform macular scar)

FamilyHPOFreeText: Onset of decreased central vision was seen in the 8th decade of life (between the ages of 71 and 75).

FamilyNotHPOs: HP:0007994 (Peripheral visual field loss)

FamilyNotHPOFreeText: Although central vision was decreased, peripheral fundi remained uninvolved.

CountryOrigin: Japan

Family#PreviousTesting: PCR-based heteroduplex analysis using gel electophoresis

Family#GenotypingMethod: Sanger sequencing

Affected: 3

Unaffected: 0

Segregations: N/A

PublishedLOD: N/A

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Tabata_1998_Family_Ue_patient_1

Variant: NM_000362.5:c.439-2dup (TIMP3) is predicted to disrupt a splice acceptor site at the junction of intron 4 and exon 5.

CAID: CA1139771334

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: While Family Ue and Family Ch are two distinct families, united by the NM_000362.5:c.439-2dup (TIMP3) variant harbored by their affected family members, they share a geographical place of origin within Japan (PMID:9760202).

FamilyPMIDs: N/A

Case#: Chen_2014_Proband_S01, male, age 20 years at onset, age 53 years at time of report, family origin reported as Chinese

CasePresentingHPOs: Nyctalopia HP:0000662, Constriction of peripheral visual field HP:0001133, Severely reduced visual acuity HP:0001141, Undetectable electroretinogram HP:0000550, Retinal degeneration HP:0000546, Macular degeneration HP:0000608, Optic disc pallor HP:0000543, Attenuation of retinal blood vessels HP:0007843, Pigmentary retinopathy HP:0000580

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa. Patient fibroblasts showed 92.58% decreased expression of PRPF4.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband included next-generation sequencing targeted to a large number of known variants in all known retinal disease-related genes.

CaseMethod1: next-generation sequencing

CaseMethod2: Sanger sequencing of PRPF4

CaseGenotypingMethod: Genotyping of the proband included next-generation sequencing targeted to a large number of known variants in all known retinal disease-related genes, followed by Sanger sequencing analysis of all coding regions of PRPF4.

Variant: The proband harbors the NM_004697.4(PRPF4):c.-114_-97del variant in the heterozygous state.

ClinVar ID: 143058

gnomAD: The NM_004697.4(PRPF4):c.-114_-97del variant is found in gnomAD v4.1.0 at a frequency of 0.0003297 (13 alleles / 39430 total alleles, with 0 homozygotes) in the East Asian population https://gnomad.broadinstitute.org/variant/9-113275629-TTGTCAGTGACGCACTTCC-T?dataset=gnomad_r4

VariantEvidence: NM_004697.4(PRPF4):c.-114_-97del is a deletion variant within the 5' UTR that disrupts the beginning of the transcribed region. Luciferase assay indicates that the ability of the PRPF4 promoter to activate transcription of the reporter gene was significantly decreased by the variant, which disrupted binding sites for the c-Ets-1 and GR-alpha transcription factors and matched the 93% decrease in PRPF4 expression seen in the patient blood cells (Figure 3).

CaseAddInfo: The proband has an unaffected son who does not harbor the variant.

CasePMIDs: N/A

FamilyLabel: Morimura_1998_Family_7828

FamilyPresentingHPOs: HP:0000546 (Retinal degeneration)

FamilyPresentingHPOFreeText: While specific phenotypes are not provided, the diagnosis of retinitis pigmentosa indicates that the affected family members maintained central vision during the first decade of life and subsequently experienced severe vision loss.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: The Dominican Republic

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

Family#GenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing in the probands and their family members.

Affected: 5

Unaffected: 5

Segregations: The pedigree (Figure 2A) shows 10 segregations, with none inconsistent.

PublishedLOD: N/A

eLOD: 3.03

AddSegregationInfo: While four of the affected family members are compound heterozygotes at the RPE65 locus, one harbors homozygous variants.

ProbandLabel: Morimura_1998_Patient_III-4

Variant: Four affected individuals are compound heterozygotes harboring the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) and NM_000329.3(RPE65):c.1207_1210dup (p.Glu404fs) variants, while one affected individual is homozygous for the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) variant.

ClinVar: 13118, 98831

gnomAD: Neither the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) variant nor the NM_000329.3(RPE65):c.1207_1210dup (p.Glu404fs) variant is found within gnomAD.

FamilyAddInfo: The two variants were confirmed to be in trans, and heterozygous carriers were found to be unaffected. Potential consanguinity between the parents was not reported, at least within the first generation of the pedigree.

FamilyPMIDs: N/A

Case#: Morimura_1998_Family_7775_Patient_II-1, female, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.

Variant: The proband is a homozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant.

ClinVar: 13115 (homozygous)

gnomAD: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant has a maximum allele frequency of 0.0002406 (within the African / African-American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68910541-G-A

VariantEvidence: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant was also detected in this publication in a heterozygous state within two apparently unrelated probands with Retinitis pigmentosa (Figure 2A) and Leber congenital amaurosis (Figure 2B), respectively. A separate publication (PMID: 16754667) expressed this missense variant in non-patient cells and showed that it abolished the isomerohydrolase activity of the protein product, reduced its stability, and shifted the subcellular localization from predominantly membrane-associated to predominantly cytosolic.

CaseAddInfo: Genotyping of the proband's mother revealed NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) in a heterozygous state. The father was not genotyped. Potential consanguinity between the parents was not reported.

CasePMIDs: N/A

Case#: Morimura_1998_Family_9148_Patient_II-1, male, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.

Variant: The proband is a compound heterozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.118G>A (p.Gly40Ser) and NM_000329.3(RPE65):c.544C>T (p.His182Tyr) variants.

ClinVar: 98830, 98875

gnomAD: The NM_000329.3(RPE65):c.2T>C (p.Met1Thr) variant has a maximum allele frequency of 0.00009643 (within the Ashkenazi Jewish population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68912520-C-T The NM_000329.3(RPE65):c.544C>T (p.His182Tyr) variant has a maximum allele frequency of 0.00009925 (within the Ashkenazi Jewish population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68906635-G-A

VariantEvidence: The paternal NM_000329.3(RPE65):c.118G>A (p.Gly40Ser) and maternal NM_000329.3(RPE65):c.544C>T (p.His182Tyr) variants are missense variants that do not have evidence of gene impact.

CaseAddInfo: Genotyping of family members revealed the two variants to be in trans. The brother of the proband shares the same genotype and diagnosis of Leber congenital amaurosis.

CasePMIDs: N/A

Case#: Morimura_1998_Family_3867_Patient_II-1, female, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.

Variant: The proband is a compound heterozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) and NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) variants.

ClinVar: 13115, 98862

gnomAD: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant has a maximum allele frequency of 0.0002406 (within the African / African-American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68910541-G-A The NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) variant is not found within gnomAD.

VariantEvidence: NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) is a missense variant that does not have evidence of gene impact. The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant was also detected in this publication in a heterozygous state within two apparently unrelated probands with Retinitis pigmentosa (Figure 2A) and Leber congenital amaurosis (Figure 2B), respectively. A separate publication (PMID: 16754667) expressed this missense variant in non-patient cells and showed that it abolished the isomerohydrolase activity of the protein product, reduced its stability, and shifted the subcellular localization from predominantly membrane-associated to predominantly cytosolic.

CaseAddInfo: Genotyping of the proband's parents revealed NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) as the paternal variant and NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) as a de novo variant.

CasePMIDs: N/A

Case#: Schiaffino_1995_Family_2948_Patient_BA442, male, age not reported, family origin reported as British in two previous publications

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been diagnosed with ocular albinism 1.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The patient's family was included in two previous linkage mapping studies (PMID: 1355560, PMID: 8301646).

CaseMethod1: Linkage mapping

CaseMethod2: Sanger sequencing

CaseGenotypingMethod: The patient's family was included in two previous linkage mapping studies (PMID: 1355560, PMID: 8301646), and the proband was genotyped in this study by Sanger sequencing of PCR products from the 9 exons of GPR143.

Variant: The proband harbors the NM_000273.3(GPR143):c.216_232del (p.Ala73fs) variant in the hemizygous state.

ClinVar: 98619

gnomAD: This variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_000273.3(GPR143):c.216_232del (p.Ala73fs) is a frameshift variant in exon 1 of 9, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 82% of the protein product.

CaseAddInfo: The variant observed in this proband has been previously reported in two other studies (PMID: 1355560, PMID: 8301646).

CasePMIDs: PMID: 1355560, PMID: 8301646

Case#: Collin_2008_Family_A_Patient_II-1, male, 61 years of age at time of study, 12 years of age at onset, family ethnicity likely to be of Dutch origin based on the description of the majority of the cohort as Dutch

CasePresentingHPOs: Nyctalopia HP:0000662, Bone spicule pigmentation of the retina HP:0007737, Attenuation of retinal blood vessels HP:0007843, Constriction of peripheral visual field HP:0001133, Undetectable electroretinogram HP:0000550, Posterior subcapsular cataract HP:0007787, Optic disc pallor HP:0000543, Peripheral retinal atrophy HP:0200070, Reduced visual acuity HP:0007663

CaseHPOFreeText: The patient has been diagnosed with retinitis pigmentosa and has been described as displaying abnormalities characteristic of this diagnosis. Night blindness was the initial symptom.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Because of the autosomal recessive pattern of inheritance in the patient's family, he and his family members were subjected to homozygosity mapping, identifying a homozygous region on chromosome 6 shared by affected members.

CaseMethod1: Homozygosity mapping within the family

CaseMethod2: Sanger sequencing of 44 PCR-amplified exons from the EYS locus

CaseGenotypingMethod: The proband was genotyped by homozygosity mapping of family members, followed by Sanger sequencing of 44 PCR-amplified exons from the EYS locus.

Variant: The proband harbors the NM_001142800.2(EYS):c.9405T>A (p.Tyr3135Ter) variant in the homozygous state.

ClinVar: 538

gnomAD: NM_001142800.2(EYS):c.9405T>A (p.Tyr3135Ter) is found in gnomAD v2.1.1 at a frequency of 0.00004991 (1/20038) in the Latino / Admixed American population https://gnomad.broadinstitute.org/variant/6-64430522-A-T

VariantEvidence: NM_001142800.2(EYS):c.9405T>A (p.Tyr3135Ter) is a nonsense variant in exon 44 of 44 that is not predicted to trigger nonsense-mediated decay but rather to disrupt the C-terminal 1% of the protein product.

CaseAddInfo: The proband is a member of Family A and has a similarly affected sister sharing the same genotype, as well as four unaffected siblings who are either heterozygous carriers or non-carriers of the variant.

CasePMIDs: N/A

Case#: Bandah-Rozenfeld_2010_NAP1_proband, female, age 30 years at time of diagnosis, in the 6th decade of life at the time of report, national origin reported as Italian

CasePresentingHPOs: HP:0007401 (Macular atrophy), HP:0032122 (Very low visual acuity), HP:0000577 (Exotropia), HP:0000639 (Nystagmus), HP:0007787 (Posterior subcapsular cataract), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: The patient has been diagnosed with advanced retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of autozygosity mapping.

CaseMethod1: Homozygosity mapping

CaseMethod2: Sanger sequencing of the 19 exons of the IMPG2 gene

CaseGenotypingMethod: Genotyping consisted of autozygosity mapping followed by Sanger sequencing of the 19 exons of the IMPG2 gene.

Variant: The patient harbors the NM_016247.4(IMPG2):c.2890C>T (p.Arg964Ter) variant in the homozygous state.

ClinVar: 3549

gnomAD: The NM_016247.4(IMPG2):c.2890C>T (p.Arg964Ter) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.00006152 (1/16256, with 0 homozygotes) in the African / African-American population. https://gnomad.broadinstitute.org/variant/3-100961664-G-A

VariantEvidence: NM_016247.4(IMPG2):c.2890C>T (p.Arg964Ter) is a nonsense variant in exon 14 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 22% of the protein product.

CaseAddInfo: The family is consanguineous, with the parents being second cousins.

CasePMIDs: N/A

Case#: Ayyagari_2002_Family_UM:F1088_Patient_III-16, male, 48 years old, ethnicity not descibed

CasePresentingHPOs: HP:0007401 (Macular atrophy), HP:0007663 (Reduced visual acuity), HP:0000529 (Progressive visual loss), HP:0007722 (Retinal pigment epithelial atrophy), HP:0003596 (Middle age onset), HP:0031624 (Moderate myopia), HP:0000603 (Central scotoma)

CaseHPOFreeText: Onset of symptoms was approximately at age 43. The proband has been diagnosed with atrophic macular degeneration, with the family exhibiting X-linked pattern of inheritance.

CaseNotHPOs: HP:0000580 (Pigmentary retinopathy), HP:0030491 (Choriocapillaris atrophy), HP:0008046 (Abnormal retinal vascular morphology), HP:0000512 (Abnormal electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and family members were subjected to linkage analysis using microsatellite markers along the length of the X chromosome (LOD score of 4.17 associated with marker DXS1058.

CaseMethod1: Sanger sequencing of the PCR-amplified exons from the NYX locus

CaseMethod2: Sanger sequencing of the PCR-amplified exons from the RPGR locus

CaseGenotypingMethod: The proband and his family members were subjected to linkage analysis using microsatellite markers along the length of the X chromosome, followed by Sanger sequencing of the PCR-amplified exons from the NYX and RPGR loci.

Variant: The proband harbors the NM_001034853.2(RPGR):c.2917G>T (p.Glu973Ter) variant in the hemizygous state.

ClinVar: 866129

gnomAD: The variant was not found in gnomAD v.2.1.1.

VariantEvidence: NM_001034853.2(RPGR):c.2917G>T (p.Glu973Ter) is a nonsense variant in the final exon (exon 15) that is not predicted to trigger nonsense-mediated decay but truncates ~16% of the C-terminus of the protein product.

CaseAddInfo: The proband is a member of Family UM:F1088, shown in Figure 1 from this study. Ten other genotype-positive affected males are present in his extended family, as well as carrier females affected with mild perimacular RPE depigmentation and tapetal reflex.

CasePMIDs: N/A

Case#: Kelsell_1998_CORD6_Family_Proband, male, age 48 at time of report, nationality listed as British

CasePresentingHPOs: HP:0000548 (Cone/cone-rod dystrophy), HP:0007663 (Reduced visual acuity), HP:0007994 (Peripheral visual field loss), HP:0000613 (Photophobia), HP:0011504 (Bull's eye maculopathy), HP:0030465 (Undetectable light-adapted electroretinogram), HP:0030469 (Abnormal dark-adapted electroretinogram)

CaseHPOFreeText: The text asserts that In all members of the proband's family, central vision was lost before age 7, while peripheral field vision was lost by the fourth decade of life. Cone ERG was undetectable early on in the disease, while rod ERG abnormalities later developed progressively.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: In a previous publication (PMID: 9097965), the family was subjected to (genome-wide) linkage analysis mapping the affected phenotype to chromosome 17p12-p13. The LOD score associated with marker locus D17S1844 was 5.93 (with no recombination).

CaseMethod1: Sanger sequencing of PCR products from each of the 18 exons of the GUCY2D locus

CaseMethod2: HhaI restriction digest of the PCR-amplified exon 13

CaseGenotypingMethod: The proband and his family members were subjected to sequencing of PCR products from each of the 18 exons of the GUCY2D locus. The PCR-amplified product from exon 13 was then subjected to HhaI restriction digest and resolved by agarose gel electrophoresis.

Variant: The proband harbors the NM_000180.3(GUCY2D):c.[2511G>C;2512C>A] variant in the heterozygous state.

ClinVar: 453243

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.3(GUCY2D):c.[2511G>C;2512C>A] is a missense variant that causes two adjacent substitutions at the protein level (p.Glu837Asp;Arg838Ser), located within the coiled-coil domain that mediates dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565). The p.Arg838Ser substitution has also been shown to disrupt the calcium-dependent regulation of GUCY2D by GUCA1A (PMID: 15504042), decrease sensitivity to inhibition by RD3 (PMID: 27703005), and trigger blindness in a transgenic mouse model (PMID: 27703005).

CaseAddInfo: The family's variant was not comprehensively genotyped in this publication but was later identified in PMID: 10647719.

CasePMIDs: PMID: 9097965, PMID: 10647719, PMID: 11565546

Case#: Kelsell_1998_CORD6_Family_2_Proband, female, age 45 at time of report, nationality listed as British

CasePresentingHPOs: HP:0007401 (Macular atrophy), HP:0000548 (Cone/cone-rod dystrophy)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing of PCR products from each of the 18 exons of the GUCY2D locus

CaseMethod2: HhaI restriction digest of the PCR-amplified exon 13

CaseGenotypingMethod: The proband and her family members were subjected to sequencing of PCR products from each of the 18 exons of the GUCY2D locus. The PCR-amplified product from exon 13 was then subjected to HhaI restriction digest and resolved by agarose gel electrophoresis.

Variant: The proband harbors the NM_000180.4(GUCY2D):c.2512C>T (p.Arg838Cys) variant in the heterozygous state.

ClinVar: 9355

gnomAD: The variant is present in gnomAD at a frequency of 0.000007744 (1/129124) in the European non-Finnish population, with no homozygotes. https://gnomad.broadinstitute.org/variant/17-7918018-C-T

VariantEvidence: NM_000180.4(GUCY2D):c.2512C>T (p.Arg838Cys) is a missense variant located within the coiled-coil domain that mediates GUCY2D dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565). The p.Arg838Cys substitution has been shown to disrupt the calcium sensitivity of GUCY2D and to trigger the inability to inactivate cyclase activity at high physiological calcium ion concentrations (PMID: 11115851).

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Family_11864_Proband_II-2, onset before age 7 years, male, seen at a medical center in Guangzhou

CasePresentingHPOs: High myopia HP:0011003, Blurred vision HP:0000622, Childhood onset HP:0011463, Protanopia HP:0011522

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of early onset high myopia, with onset in early childhood and either high myopia or axial length >25 mm before age 7, or refractive errors <-10 as an adult.

CaseNotHPOs: Nystagmus HP:0000639, Photophobia HP:0000613, Nyctalopia HP:0000662

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping of the proband was performed by either targeted exome sequencing or whole exome sequencing.

CaseMethod1: targeted exome or whole exome sequencing

CaseMethod2: Sanger sequencing of OPN1LW

CaseGenotypingMethod: Genotyping of the proband was performed by either targeted exome sequencing or whole exome sequencing, followed by Sanger sequencing of OPN1LW.

Variant: The individual harbors the NM_020061.6(OPN1LW):c.427_433dup (p.Ala145ValfsTer23) variant in the hemizygous state.

CAID: CA2695237718

gnomAD: The variant was not found in gnomAD version 4.1.0.

VariantEvidence: NM_020061.6(OPN1LW):c.427_433dup (p.Ala145ValfsTer23) is a nonsense variant in exon 3 of 6 that is predicted to undergo nonsense-mediated decay.

CaseAddInfo: The proband was seen at a medical center in Guangzhou. The variant was inherited from the proband's unaffected mother.

CasePMIDs: N/A

Case#: Family_11850_Proband_II-2, onset before age 7 years, male, seen at a medical center in Guangzhou

CasePresentingHPOs: High myopia HP:0011003, Blurred vision HP:0000622, Childhood onset HP:0011463, Protanopia HP:0011522

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of early onset high myopia, with onset in early childhood and either high myopia or axial length >25 mm before age 7, or refractive errors <-10 as an adult.

CaseNotHPOs: Nystagmus HP:0000639, Photophobia HP:0000613, Nyctalopia HP:0000662

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping of the proband was performed by either targeted exome sequencing or whole exome sequencing.

CaseMethod1: targeted exome or whole exome sequencing

CaseMethod2: Sanger sequencing of OPN1LW

CaseGenotypingMethod: Genotyping of the proband was performed by either targeted exome sequencing or whole exome sequencing, followed by Sanger sequencing of OPN1LW.

Variant: The individual harbors the NM_020061.6(OPN1LW):c.518_519insC (p.Ala174CysfsTer?) variant in the hemizygous state.

CAID: CA3071606830

gnomAD: The variant was not found in gnomAD version 4.1.0.

VariantEvidence: NM_020061.6(OPN1LW):c.518_519insC (p.Ala174CysfsTer?) is a nonsense variant in exon 3 of 6 that is predicted to undergo nonsense-mediated decay.

CaseAddInfo: The proband was seen at a medical center in Guangzhou. The variant was inherited from the proband's unaffected mother.

CasePMIDs: N/A

Case#: Family_9073_Proband_III-1, onset before age 7 years, male, seen at a medical center in Guangzhou

CasePresentingHPOs: High myopia HP:0011003, Blurred vision HP:0000622, Childhood onset HP:0011463, Protanopia HP:0011522

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of early onset high myopia, with onset in early childhood and either high myopia or axial length >25 mm before age 7, or refractive errors <-10 as an adult.

CaseNotHPOs: Nystagmus HP:0000639, Photophobia HP:0000613, Nyctalopia HP:0000662

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping of the proband was performed by either targeted exome sequencing or whole exome sequencing.

CaseMethod1: targeted exome or whole exome sequencing

CaseMethod2: Sanger sequencing of OPN1LW

CaseGenotypingMethod: Genotyping of the proband was performed by either targeted exome sequencing or whole exome sequencing, followed by Sanger sequencing of OPN1LW.

Variant: The individual harbors the NM_020061.6:c.757C>T (p.Gln253Ter) variant in the hemizygous state.

CAID: CA415307744

gnomAD: The variant was not found in gnomAD version 4.1.0.

VariantEvidence: NM_020061.6:c.757C>T (p.Gln253Ter) is a nonsense variant in exon 5 of 6 that is predicted to undergo nonsense-mediated decay.

CaseAddInfo: The proband was seen at a medical center in Guangzhou. A maternal uncle is similarly affected but ungenotyped.

CasePMIDs: N/A

FamilyLabel: Gliem_2015_Family_3

Family#PresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy), HP:0011506 (Choroidal neovascularization)

FamilyHPOFreeText: Onset of symptoms in the early fourth or fifth decade of life, with dark adaptation problems being the first symptoms, central and/or midperipheral chorioretinal atrophy, and central fibrosis or focal fibrotic changes, thinning of choroid

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Germany

Family#PreviousTesting: Targeted next-generation sequencing of the proband (for a 74-gene panel of retinal dystrophy genes), identifying the TIMP3 variant as well as a heterozygous c.1107G>A (p.Trp369) variant in RP1L1*

Family#GenotypingMethod: Sanger sequencing of PCR products from the TIMP3 and RP1L1 genes, confirming that the TIMP3 variant co-segregated with the disease.

Affected: 2

Unaffected: 2

Segregations: 2

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: The number of affected individuals / segregations was insufficient to estimate a LOD score.

ProbandLabel: Gliem_2000_Family_3_patient_III.5

Variant: Patients harbor the NM_000362.5(TIMP3):c.452A>G (p.Tyr151Cys) missense variant.

CAID: CA411540149

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

Case: Gliem_2000_Family_2_patient_V.1, male, country of origin Germany, onset at 51 years of age

DiseaseAssertion: Sorsby fundus dystrophy

FamilyInfo: The variant was inherited by the proband rather than acquired de novo.

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy), HP:0012508, (Metamorphopsia), HP:0000662 (Nyctalopia)

CaseHPOFreeText: Presentation at age 51 with visual loss. Evaluation at age 71 found widespread central and midperipheral chorioretinal atrophy, thinning of the choroid in areas of atrophy, central focal subretinal fibrosis at the posterior pole, metamorphopsia (with onset in the sixth decade of life), and nyctalopia that was only developed late in disease progression.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Phenotypic characterization only

GenotypingMethod: Sanger sequencing of PCR products from all 5 exons and flanking splice junctions of the TIMP3 gene.

PreviouslyPublished: Some of the family members were previously identified by genotyping as having Sorsby fundus dystrophy (PMID:25390527), and are more extensively phenotypically described in this study.

SupplementalData: N/A

Variant: Patients harbor the NM_000362.5(TIMP3):c.545A>G (p.Tyr182Cys) missense variant.

CAID: CA411540365

gnomAD: Variant is absent from gnomAD.

VariantEvidence: This missense variant within exon 5 of TIMP3 results in an unpaired Cys residue.

Case: Gliem_2000_Family_1_patient_II.1, female, country of origin Germany, onset at 47 years of age

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: The variant was inherited by the proband rather than acquired de novo.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy)

CaseHPOFreeText: Presentation at age 47 with nyctalopia. Evaluation at age 61 showed drusen deposits in macular area, near optic disk and along vascular arcades, central and midperipheral atrophy, and reduced choroidal thickness.

CaseNOTHPOs: HP:0011506 (Choroidal neovascularization)

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Phenotypic characterization only

GenotypingMethod: Sanger sequencing of PCR products from all 5 exons and flanking splice junctions of the TIMP3 gene.

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Proband harbors the NM_000362.5(TIMP3):c.530A>G (p.Tyr177Cys) missense variant.

CAID: CA411540328

gnomAD: Variant is absent from gnomAD.

VariantEvidence: This missense variant within exon 5 of TIMP3 results in an unpaired Cys residue.

Group Phenotypes

GroupName: Gliem_2015_Group_1

GroupPresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0000533 (Chorioretinal atrophy), HP:0000662 (Nyctalopia)

GroupHPOFreeText: Central and midperipheral atrophy, Central fibrosis, Dark adaptation problems, Progressive loss of visual acuity

GroupNotHPOs: N/A

GroupDemographics

NumberMales: 7

NumberFemales: 13

CountryOrigin: Germany

Ethnicity: Not mentioned

Race: Not mentioned

AgeRange: 52-79 at time of evaluation

TotalNumber: 20

GroupPreviousTesting: N/A

GroupGenotypingMethod Sanger sequencing of PCR products from all 5 exons and flanking splice junctions of the TIMP3 gene.

GroupAddInfo: The group consisted of 3 unrelated families.

Case#: Delvallée_2021_Proband_D.II-2, female, age not described, family origin reported as from Denmark and Sweden, ancestry reported as European

CasePresentingHPOs: HP:0000556 (Retinal dystrophy), HP:0001162 (Postaxial hand polydactyly), HP:0030084 (Clinodactyly), HP:0001513 (Obesity), HP:0000119 (Abnormality of the genitourinary system)

CaseHPOFreeText: The proband additionally exhibits slow ideation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was subjected to targeted exome sequencing to detect variants in BBS-related loci.

CaseMethod1: targeted exome sequencing

CaseMethod2: Sanger sequencing of BBS1

CaseGenotypingMethod: The proband was subjected to targeted exome sequencing to detect variants in BBS-related loci, followed by Sanger sequencing of BBS1 to identify the variant and perform segregation analysis within the family.

Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) and NM_024649.5(BBS1):c.1214_1215insSVA variants in the compound heterozygous state.

ClinVar ID: 12143, 981241

gnomAD: The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1 The NM_024649.5(BBS1):c.1214_1215insSVA was not found in gnomAD v2.1.1.

VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant. NM_024649.5(BBS1):c.1214_1215insSVA is an indel in exon 13 of 17 that is reported to shift the reading frame and trigger nonsense-mediated decay. Figure 3 confirms the likely occurrences of NMD by indicating that the compound heterozygous probands have approximately 50% of wild-type levels of both BBS1 mRNA and protein.

CaseAddInfo: The proband's family indicates segregation of the two variants from the two heterozygous unaffected carrier parents.

CasePMIDs: N/A

Case#: Delvallée_2021_Proband_B.II-1, male, age not described, family origin reported as from western France, ancestry reported as European

CasePresentingHPOs: HP:0000556 (Retinal dystrophy), HP:0000639 (Nystagmus), HP:0001162 (Postaxial hand polydactyly), HP:0001156 (Brachydactyly), HP:0001513 (Obesity), HP:0001256 (Intellectual disability, mild), HP:0001270 (Motor delay), HP:0000054 (Micropenis), HP:0000028 (Cryptorchidism)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was subjected to targeted exome sequencing to detect variants in BBS-related loci.

CaseMethod1: targeted exome sequencing

CaseMethod2: Sanger sequencing of BBS1

CaseGenotypingMethod: The proband was subjected to targeted exome sequencing to detect variants in BBS-related loci, followed by Sanger sequencing of BBS1 to identify the variant and perform segregation analysis within the family.

Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) and NM_024649.5(BBS1):c.1214_1215insSVA variants in the compound heterozygous state.

ClinVar ID: 12143, 981241

gnomAD: The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1 The NM_024649.5(BBS1):c.1214_1215insSVA was not found in gnomAD v2.1.1.

VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant. NM_024649.5(BBS1):c.1214_1215insSVA is an indel in exon 13 of 17 that is reported to shift the reading frame and trigger nonsense-mediated decay. Figure 3 confirms the likely occurrences of NMD by indicating that the compound heterozygous probands have approximately 50% of wild-type levels of both BBS1 mRNA and protein.

CaseAddInfo: The proband's family includes two similarly affected brothers sharing the same genotype.

CasePMIDs: N/A

Case#: Thiadens_2009_Family_A_Proband_AII-2, male, age 6 years at onset and 51 years at the time of report, sites of treatment listed as the Netherlands, Belgium, U.K., or Canada

CasePresentingHPOs: HP:0030534 (Abnormal best corrected visual acuity test), HP:0000613 (Photophobia), HP:0000639 (Nystagmus), HP:0011003 (High myopia), HP:0000551 (Color vision defect, described as severe), HP:0030825 (Absent foveal reflex), HP:0007703 (Abnormality of retinal pigmentation, described as mild), HP:0030465 (Undetectable light-adapted electroretinogram)

CaseHPOFreeText: The proband and affected family member were previously diagnosed with early onset autosomal recessive cone dystrophy. The proband had onset by age 6 years.

CaseNotHPOs: HP:0007769 (Peripheral retinal degeneration)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Affected and unaffected family members were initially subjected to homozygosity mapping based on Affymetrix GeneChIP SNP analysis, identifying an 11-Mb region of homozygosity shared with another unrelated family.

CaseMethod1: homozygosity mapping

CaseMethod2: screening of the 22 exons and flanking regions of PDE6C (the only strong candidate gene) using Sanger sequencing

CaseGenotypingMethod: Affected and unaffected family members were initially subjected to homozygosity mapping based on Affymetrix GeneChIP SNP analysis, identifying an 11-Mb region of homozygosity shared with another unrelated family. The clear candidate gene, PDE6C, was then subjected to Sanger sequencing-based screening of the 22 exons and flanking regions.

Variant: The proband harbors the NM_006204.4(PDE6C):c.85C>T (p.Arg29Trp) variant in the homozygous state.

ClinVar ID: 8763

gnomAD: The NM_006204.4(PDE6C):c.85C>T (p.Arg29Trp) variant is found in gnomAD v2.1.1 at a frequency of 0.00008009 (2/24972) in the African / African-American population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/10-95372567-C-T

VariantEvidence: NM_006204.4(PDE6C):c.85C>T (p.Arg29Trp) is a missense variant that does not have experimental evidence of a functional effect on the protein product. However, it has been reported in similarly affected individuals in other studies (PMID: 21127010, PMID: 30080950).

CaseAddInfo: The patient's affected sibling shares the same homozygous genotype, while the parents are unaffected and unrelated at least during the last 3 generations.

CasePMIDs: N/A

Case#: Weigell-Weber_2000_adCRD_Family_Proband, age and gender not specified, nationality listed as Swiss

CasePresentingHPOs: HP:0000548 (Cone/cone-rod dystrophy), HP:0007663 (Reduced visual acuity), HP:0000512 (Abnormal electroretinogram), HP:0000529 (Progressive visual loss), HP:0001123 (Visual field defect), HP:0000613 (Photophobia)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and family members were subjected to linkage analysis excluding linkage to candidate loci at chr19q13, chr6q13-q15, and chr6p21, and confirming linkage to chr17p (using the microsatellite

CaseMethod1: Sanger sequencing of PCR products from each of the GUCY2D locus

CaseMethod2: HhaI restriction digest of the PCR-amplified exon 13

CaseGenotypingMethod: The proband and his family members were subjected to sequencing of PCR products from each of the 18 exons of the GUCY2D locus. The PCR-amplified product from exon 13 was then subjected to HhaI restriction digest and resolved by agarose gel electrophoresis.

Variant: The proband harbors the NM_000180.4(GUCY2D):c.2513G>A (p.Arg838His) variant in the heterozygous state.

ClinVar: 9357

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.4(GUCY2D):c.2513G>A (p.Arg838His) is a missense variant located within the coiled-coil domain that mediates dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565). The p.Arg838His substitution has been shown to disrupt the calcium sensitivity of GUCY2D and to trigger the inability to inactivate cyclase activity at high physiological calcium ion concentrations (PMID: 11115851).

CaseAddInfo: N/A

CasePMIDs: N/A

FamilyLabel: Olivier_2021_Family_A

Family#PresentingHPOs: HP:0030629 (Perifoveal ring of hyperautofluorescence), HP:0011510 (Drusen),

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with retinitis pigmentosa, with severity ranging from mild to severe, depending on the family member.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: Younger family members were thought to be "pre-clinical", with only mild symptoms such as a subtle non-physiological autofluorescence ring and some drusen-like lesions in the posterior pole.

CountryOrigin: The family is reportedly French.

Ethnicity: Not specifically described

Race: N/A

Family#PreviousTesting: Panel-based genetic testing was performed, focusing on retinitis pigmentosa-associated genes. Subsequent testing used whole exome sequencing of four affected and one unaffected patient (II:1, II:2, II:3, III:3 and III:4).

Family#Method1: whole-exome sequencing

Family#Method2: Sanger sequencing of the candidate genes is assumed but not described.

Family#GenotypingMethod: Panel-based genetic testing was performed, focusing on retinitis pigmentosa-associated genes. Subsequent testing used whole exome sequencing of four affected and one unaffected patient (II:1, II:2, II:3, III:3 and III:4). Sanger sequencing of the candidate genes is assumed but not described.

Affected: 10 genotyped

Unaffected: 4 genotyped

Segregations: 9 segregations are shown by the pedigree in Figure 1.

PublishedLOD: N/A

eLOD: 2.7

AddSegregationInfo: All genotype-positive individuals were phenotype-positive in this family.

ProbandLabel: Olivier_2021_Family_Proband_IV-8

Variant: The affected family members harbor the NM_001563.4:c.1824+1G>A variant in the heterozygous state.

CAID: CA3898050

gnomAD: This variant is found in gnomAD v2.1.1 at a frequency of 0.00002980 (1 / 33554 alleles total in the Latino / Admixed American population. https://gnomad.broadinstitute.org/variant/6-76660278-C-T

VariantEvidence: NM_001563.4:c.1824+1G>A is a canonical splice site variant predicted to have a severe impact on the gene product.

FamilyAddInfo: The family's national origin has been reported as French.

FamilyPMIDs: N/A

Case#: Olivier_2021_Family_D_Proband_II:2, male, age 58 years at the time of report, national origin reported as Spanish

CasePresentingHPOs: HP:0007737 (Bone spicule pigmentation of the retina), HP:0007843 (Attenuation of retinal blood vessels), HP:0030629 (Perifoveal ring of hyperautofluorescence)

CaseHPOFreeText: The proband and his sibling have been diagnosed with autosomal recessive retinitis pigmentosa, with clinical signs in the fundus reportedly consistent with this diagnosis.

CaseNotHPOs: HP:0040049 (Macular edema), HP:0030500 (Yellow/white lesions of the macula)

CaseNotHPOFreeText: N/A

CasePreviousTesting: It is not clear whether previous testing methods included systematic genotyping of loci associated with VMD or RP.

CaseMethod1: Screening of IMPG1 using either gene panel testing or exome sequencing

CaseMethod2: Sanger sequencing-based confirmation

CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus and Sanger sequencing-based confirmation.

Variant: The proband harbors the NM_001563.4(IMPG1):c.1875A>G (p.Ile625Met) variant in the homozygous state.

CAID: CA364775681

gnomAD: This variant is not found in gnomAD v2.1.1.

VariantEvidence: NM_001563.4(IMPG1):c.1875A>G (p.Ile625Met) is a missense variant that lacks evidence of a functional impact on the protein product.

CaseAddInfo: The patient's sister is similarly affected with the same homozygous genotype, while an unaffected sister harbored the variant in the heterozygous state. Parental consanguinity is not reported but family origin is from a small village.

CasePMIDs: N/A

Case#: Olivier_2021_Family_K_Proband_II:3, male, age 43 years at the time of onset, national origin reported as Spanish

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0001099 (Fundus atrophy), HP:0007737 (Bone spicule pigmentation of the retina)

CaseHPOFreeText: The proband has onset of retinitis pigmentosa at the age of 43 years.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: It is not clear whether previous testing methods included systematic genotyping of loci associated with VMD or RP.

CaseMethod1: Screening of IMPG1 using either gene panel testing or exome sequencing

CaseMethod2: Sanger sequencing-based confirmation

CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus and Sanger sequencing-based confirmation.

Variant: The proband harbors the NM_001563.4(IMPG1):c.1982G>A (p.Arg661His) variant in the homozygous state.

ClinVar ID: 1056230

gnomAD: The NM_001563.4(IMPG1):c.1982G>A (p.Arg661His) variant is found in gnomAD v2.1.1 at a frequency of 0.00004006 (1/24964) in the African / African-American population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76657093-C-T

VariantEvidence: NM_001563.4(IMPG1):c.1982G>A (p.Arg661His) is a missense variant, which does not have experimental evidence of a functional effect on the protein product.

CaseAddInfo: The patient's affected sister shares the same homozygous genotype.

CasePMIDs: N/A

Case#: Olivier_2021_Family_H_Proband_II:1, male, age 53 years at the time of diagnosis, national origin reported as French

CasePresentingHPOs: HP:0007401 (Macular atrophy), HP:0007737 (Bone spicule pigmentation of the retina)

CaseHPOFreeText: The proband has been diagnosed with maculopathy at the age of 53 years, and exhibits retinal discoloration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: It is not clear whether previous testing methods included systematic genotyping of loci associated with VMD or RP.

CaseMethod1: Screening of IMPG1 using either gene panel testing or exome sequencing

CaseMethod2: Sanger sequencing-based confirmation

CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus and Sanger sequencing-based confirmation.

Variant: The proband harbors the NM_001563.4:c.2083G>T (p.Glu695Ter) variant in the heterozygous state.

CAID: CA364770054

gnomAD: This variant is not found in gnomAD v2.1.1.

VariantEvidence: NM_001563.4:c.2083G>T (p.Glu695Ter) is a nonsense variant in exon 15 of 17, which is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 13% of the protein product.

CaseAddInfo: The patient's brother is an unaffected carrier of the variant.

CasePMIDs: N/A

Case#: Sergouniotis_2011_Proband_A-2, female, age 34 years, family ethnic origin described as Middle Eastern

CasePresentingHPOs: Congenital nystagmus HP:0006934, Presenile cataracts HP:0007819, Reduced visual acuity HP:0007663, Nyctalopia HP:0000662, Constriction of peripheral visual field HP:00011

CaseHPOFreeText: The proband received a diagnosis of Leber congenital amaurosis shortly after birth. Fundoscopy results were described as "significant pigment at the level of the retinal pigment epithelium and in a configuration unlike that of typical RP".

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was initially genotyped by a combination of homozygosity mapping and exome sequencing.

CaseMethod1: homozygosity mapping and exome sequencing

CaseMethod2: Sanger sequencing of the proband and family members to confirm the presence of the variant and to test segregation

CaseGenotypingMethod: The proband was initially genotyped by a combination of homozygosity mapping and exome sequencing. Sanger sequencing of the proband and family members was then performed to confirm the presence of the variant and to test segregation.

Variant: The individual is homozygous for the NM_002242.4(KCNJ13):c.496C>T (p.Arg166Ter) variant.

ClinVar: 30331

gnomAD: The variant was not found in gnomAD version 4.1.0.

VariantEvidence: NM_002242.4(KCNJ13):c.496C>T (p.Arg166Ter) is a nonsense variant in exon 3 of 3 that is not predicted to trigger nonsense-mediated decay but rather to truncate the C-terminal 54% of the protein product.

CaseAddInfo: The proband's family history includes consanguinity and a sibling similarly diagnosed with LCA.

CasePMIDs: N/A

Case#: Sergouniotis_2011_Proband_B-3, male, age 33 years, family ethnic origin described as European

CasePresentingHPOs: Reduced visual acuity HP:0007663, Constriction of peripheral visual field HP:0001133, Infantile onset HP:0003593, Strabismus HP:0000486, Nystagmus HP:0000639, Progressive night blindness HP:0007675, Moderate myopia HP:0031624, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654, Presenile cataracts HP:0007819, Nummular pigmentation of the fundus HP:0030505, Retinal pigment epithelial loss on macular OCT HP:0030611

CaseHPOFreeText: The proband received a diagnosis of Leber congenital amaurosis. His phenotype is described as similar to the other affected individuals, including "a distinct and unusual retinal appearance and a similar early onset of visual loss, suggesting both impaired retinal development and progressive retinal degeneration, involving both rod and cone pathways". The disease was described as mildly progressive. OCT showed distorted retinal microanatomy even in areas without cell death, possibly indicating disturbance of the early development of the neurosensory retina.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was previously genotyped by screening for previously-reported LCA-causing variants by microarray chip, with no molecular diagnosis.

CaseMethod1: screening for previously-reported LCA-causing variants by microarray chip

CaseMethod2: Sanger sequencing of the KCNJ13 exons and intron-exon boundaries

CaseGenotypingMethod: The proband was previously genotyped by screening for previously-reported LCA-causing variants by microarray chip, with no molecular diagnosis. Sanger sequencing of the KCNJ13 exons and intron-exon boundaries was subsequently performed.

Variant: The individual is homozygous for the NM_002242.4(KCNJ13):c.722T>C (p.Leu241Pro) variant.

ClinVar: 30332

gnomAD: The variant was not found in gnomAD version 4.1.0.

VariantEvidence: NM_002242.4(KCNJ13):c.722T>C (p.Leu241Pro) is a missense variant that has no experimental evidence in this study but has separately been shown to severely decrease expression and abolish complex glycosylation of KCNJ13 (PMID: 30257863, Figure 10).

CaseAddInfo: The proband's family history is not known to include consanguinity but heterozygous parents originate from the same isolated geographic area.

CasePMIDs: N/A

Case#: Perrault_2012_Patient_FVII1, male, 18 months of age at time of study, ethnicity not specified

CasePresentingHPOs: HP:0001252 (Hypotonia), HP:0011968 (Feeding difficulties), HP:0003577 (Congenital onset), HP:0000639 (Nystagmus), HP:0010306 (Short thorax), HP:0000773 (Short ribs), HP:0010230 (Cone-shaped epiphyses of the phalanges of the hand), HP:0000093 (Proteinuria), HP:0001970 (Tubulointerstitial nephritis), HP:0004719 (Hyperechogenic kidneys)

CaseHPOFreeText: This proband was diagnosed with Jeune syndrome, unlike the other probands in this study who were diagnosed with Mainzer-Saldino syndrome. Limbs are described as trident. Elevated urea listed as a kidney-related phenotype.

CaseNotHPOs: HP:0025404 (Abnormal visual fixation), HP:0004322 (Short stature), HP:0000929 (Abnormal skull morphology)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)

CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140

CaseGenotypingMethod: The patient was genotyped by ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes), confirmed by Sanger sequencing of the 29 coding exons of IFT140

Variant: The patient is a compound heterozygote harboring the NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) and NM_014714.4(IFT140):c.2399+1G>T variants in IFT140.

ClinVar: 31683, 31680

gnomAD: The NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) variant is present in gnomAD at a frequency of 0.00009295 in the European (non-Finnish) population (12/129100, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1642177-C-T The NM_014714.4(IFT140):c.2399+1G>T variant is present in gnomAD at a frequency of 0.0001231 in the European (non-Finnish) population (14/113764, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1607935-C-A

VariantEvidence: Exogenous expression of the FLAG-tagged p.Gly212Arg variant in the RPE1 (retinal pigment epithelial) cell line revealed an inability to co-localize with gamma-tubulin, indicating a defect in localization to the basal body in most cells that is less severe than one of the other suspected pathogenic missense variants (Figure 3A). The NM_014714.4(IFT140):c.2399+1G>T variant disrupts a canonical splice donor site and is predicted but not confirmed to trigger skipping of exon 18/31.

CaseAddInfo: The proband's parents are reportedly non-consanguineous.

CasePMIDs: N/A

FamilyLabel: Perrault_2012_Family_FIV

Family#PresentingHPOs: HP:0003593 (Infantile onset), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity)

Family#PresentingHPOFreeText: Staining of ciliary axonemes for acetylated alpha-tubulin detected an absence of cilia in a high percentage of cultured fibroblast cells, relative to control patients. Affected family members have been diagnosed with Mainzer-Saldino syndrome.

FamilyNotHPOs: HP:0001410 (Decreased liver function), HP:0012211 (Abnormal renal physiology)

FamilyNotHPOFreeText: IFT140 protein localization along the ciliary axoneme was unaffected in patient FIV3, however, two components of the anterograde transport IFT-B complex, IFT88 and IFT46, were aberrantly localized. They were evenly distributed along the cilium instead of primarily localized at the base and the tip of the cilium, suggesting an alteration in retrograde ciliary transport.

CountryOrigin: Saudi Arabia

Ethnicity: Not described.

Race: Not described.

Family#PreviousTesting: N/A

FamilyMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)

Family#Method2: Sanger sequencing of the 29 coding exons of IFT140.

Family#GenotypingMethod: The family was genotyped by ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes), confirmed by Sanger sequencing of the 29 coding exons of IFT140

Affected: 3

Unaffected: 3

Segregations: 2 segregation were reported. The pedigree can be found in Figure S1. The family was described as consanguineous.

PublishedLOD: N/A

eLOD: 1.50

AddSegregationInfo: N/A

ProbandLabel: Perrault_2012_patient_FIV3

Variant: Affected individuals harbor the NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant in a homozygous state.

ClinVar: 31679

gnomAD: The NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant is present in gnomAD at a frequency of 0.00004031 in the African / African-American population (1/24806, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1614075-C-T

FamilyAddInfo: The parents of the affected family members are reportedly consanguineous (first cousins).

FamilyPMIDs: N/A

Case#: Perrault_2012_Patient_FII1, male, 18 years of age at time of study, ethnicity not specified

CasePresentingHPOs: HP:0003577 (Congenital onset), HP:0000639 (Nystagmus), HP:0025573 (Mild myopia), HP:0007994 (Peripheral visual field loss), HP:0007663 (Reduced visual acuity), HP:0007814 (Retinal pigment epithelial mottling), HP:0000608 (Macular degeneration), HP:0000550 (Undetectable electroretinogram), HP:0010164 (Cone-shaped epiphyses of the toes), HP:0003774 (Stage 5 chronic kidney disease), HP:0002153 (Hyperkalemia), HP:0000113 (Polycystic kidney dysplasia), HP:0000556 (Retinal dystrophy), HP:0001396 (Cholestasis), HP:0010230 (Cone-shaped epiphyses of the phalanges of the hand)

CaseHPOFreeText: Photoattraction was listed as a phenotype. Acetylated alpha-tubulin staining in cultured fibroblasts showed an absence of primary cilia in a high number of cells from this patient.

CaseNotHPOs: HP:0004322 (Short stature), HP:0000773 (Short ribs), HP:0000900 (Thickened ribs), HP:0000929 (Abnormal skull morphology), HP:0040064 (Abnormality of limbs), HP:0001263 (Global developmental delay), HP:0004979 (Metaphyseal sclerosis)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)

CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140

CaseGenotypingMethod: The patient was genotyped by ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes), confirmed by Sanger sequencing of the 29 coding exons of IFT140

Variant: The patient is a compound heterozygote harboring the NM_014714.4(IFT140):c.932A>G (p.Tyr311Cys) and NM_014714.4(IFT140):c.857_860del (p.Ile286LysfsTer6) variants in IFT140.

ClinVar: 31681

CAID: CA129888

gnomAD: Neither variant was found in gnomAD.

VariantEvidence: Exogenous expression of the FLAG-tagged p.Tyr311Cys variant in the RPE1 (retinal pigment epithelial) cell line revealed an inability to co-localize with gamma-tubulin, indicating a defect in localization to the basal body in most cells, although milder than another suspected pathogenic missense variant (Figure 3A). The p.Ile286LysfsTer6) variant is a frameshift variant in exon 8 of 31, introducing a premature stop codon predicted to trigger nonsense-mediated decay or at least disrupt the C-terminal 81% of the protein product.

CaseAddInfo: The proband's parents are reportedly non-consanguineous.

CasePMIDs: N/A

Case#: Perrault_2012_Patient_FV1, male, 10 years of age at time of study, ethnicity not specified

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000545 (Myopia), HP:0007994 (Peripheral visual field loss), HP:0032037 (Mildly reduced visual acuity), HP:0000510 (Rod-cone dystrophy), HP:0000512 (Abnormal electroretinogram), HP:0004322 (Short stature), HP:0001363 (Craniosynostosis), HP:0030799 (Scaphocephaly), HP:0001999 (Abnormal facial shape), HP:0010230 (Cone-shaped epiphyses of the phalanges of the hand), HP:0000365 (Hearing impairment), HP:0003774 (Stage 5 chronic kidney disease), HP:0000107 (Renal cyst), HP:0004719 (Hyperechogenic kidneys), HP:0005565 (Reduced renal corticomedullary differentiation), HP:0001510 (Growth delay)

CaseHPOFreeText: This proband was diagnosed with Mainzer-Saldino syndrome.

CaseNotHPOs: HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)

CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140

CaseGenotypingMethod: The patient was genotyped by ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes), confirmed by Sanger sequencing of the 29 coding exons of IFT140

Variant: The patient is a compound heterozygote harboring the NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) and NM_014714.4(IFT140):c.3916dup (p.Ala1306fs) variants in IFT140.

ClinVar: 31683, 31684

gnomAD: The NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) variant is present in gnomAD at a frequency of 0.00009295 in the European (non-Finnish) population (12/129100, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1642177-C-T The NM_014714.4(IFT140):c.3916dup (p.Ala1306fs) variant is present in gnomAD at a frequency of 0.0001210 in the African / African-American population (3/24790, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1570005-G-GC

VariantEvidence: Exogenous expression of the FLAG-tagged p.Gly212Arg variant in the RPE1 (retinal pigment epithelial) cell line revealed an inability to co-localize with gamma-tubulin, indicating a defect in localization to the basal body in most cells that is less severe than one of the other suspected pathogenic missense variants (Figure 3A). NM_014714.4(IFT140):c.3916dup (p.Ala1306fs) is a frameshift variant that introduces a premature stop codon in exon 28/31 and is predicted to trigger NMD or at least to truncate ~11% of the protein product.

CaseAddInfo: The proband's parents are reportedly non-consanguineous.

CasePMIDs: N/A

Case#: Perrault_2012_Patient_FIV3, male, 17 years of age at time of study, Saudi Arabian national origin

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0000639 (Nystagmus), HP:0000729 (Autistic behavior), HP:0001250 (Seizure), HP:0008499 (High hypermetropia), HP:0001123 (Visual field defect), HP:0007663 (Reduced visual acuity), HP:0000550 (Undetectable electroretinogram), HP:0010230 (Cone-shaped epiphyses of the phalanges of the hand), HP:0000556 (Retinal dystrophy)

CaseHPOFreeText: Acetylated alpha-tubulin staining in cultured fibroblasts showed an absence of primary cilia in a high number of cells from this patient. IFT140 protein localization along the ciliary axoneme was unaffected, however, two components of the anterograde transport IFT-B complex, IFT88 and IFT46, were aberrantly localized. They were evenly distributed along the cilium instead of primarily localized at the base and the tip of the cilium, suggesting an alteration in retrograde ciliary transport.

CaseNotHPOs: HP:0004322 (Short stature), HP:0000765 (Abnormal thorax morphology), HP:0000929 (Abnormal skull morphology), HP:0040064 (Abnormality of limbs), HP:0001410 (Decreased liver function), HP:0012211 (Abnormal renal physiology), HP:0003272 (Abnormal hip bone morphology)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)

CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140

CaseGenotypingMethod: The patient was genotyped by ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes), confirmed by Sanger sequencing of the 29 coding exons of IFT140

Variant: Affected individuals harbor the NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant in a homozygous state.

ClinVar: 31679

gnomAD: The NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant is present in gnomAD at a frequency of 0.00004031 in the African / African-American population (1/24806, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1614075-C-T

VariantEvidence: Exogenous expression of the FLAG-tagged p.Glu664Lys variant in the RPE1 (retinal pigment epithelial) cell line revealed an inability to co-localize with gamma-tubulin, indicating a relatively severe defect in localization to the basal body in most cells, relative to other suspected pathogenic missense variants and the wild-type control (Figure 3A).

CaseAddInfo: The proband's parents are reportedly consanguineous (first cousins).

CasePMIDs: N/A

Case#: Li_2015_Proband_HM429III3, onset before age 7 years, male, seen at a medical center in Guangzhou

CasePresentingHPOs: Abnormal optic disc morphology HP:0012795, Abnormal morphology of the choroidal vasculature HP:0025568, Abnormal light-adapted electroretinogram HP:0008275, Protanopia HP:0011522

CaseHPOFreeText: The proband has a diagnosis of early onset high myopia, yet also shows protanopia. He exhibits myopic fundus changes, with temporal crescent of optic nerve head and tigroid appearance of posterior retina. Rod ERG responses are normal, while cone responses are mildly to moderately reduced.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping of the proband was performed by whole exome sequencing.

CaseMethod1: whole exome sequencing

CaseMethod2: Sanger sequencing of OPN1LW

CaseGenotypingMethod: Genotyping of the proband was performed by whole exome sequencing, followed by Sanger sequencing of OPN1LW.

Variant: The individual harbors the NM_020061.6(OPN1LW):c.617_620dup (p.Phe208ArgfsTer51) variant in the hemizygous state.

CAID: CA2739290587

gnomAD: The variant was not found in gnomAD version 4.1.0.

VariantEvidence: NM_020061.6(OPN1LW):c.617_620dup (p.Phe208ArgfsTer51) is a nonsense variant in exon 4 of 6 that is predicted to undergo nonsense-mediated decay.

CaseAddInfo: The proband was seen at a medical center in Guangzhou. 4 other male family members are similarly affected but ungenotyped.

CasePMIDs: N/A

Case#: Holmberg_Patient_1, male, age 3 at onset and age 15 at time of study, Finnish origin

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0000550 (Undetectable electroretinogram), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus), HP:0001312 (Giant somatosensory evoked potentials)

CaseHPOFreeText: Age of onset was 3, while mental decline was present at age 3 and both visual deterioration and abolished ERG at age 6. The patient had progressive cerebral atrophy starting between the ages of 6 and 7. Ataxia and seizures were found at age 8. Loss of independent walking occurred at age 9. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter. Giant flash visual evoked potentials were found at age 10.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant.

ClinVar: 2564 (homozygous)

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant is 0.0008137 (within the European Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77575052-CAT-C

VariantEvidence: NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) is a recurring frameshift variant that is predicted to disrupt approximately 5% of CLN5 at the C-terminus and has been shown to disturb its localization to the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Holmberg_Patient_2, male, age 3 at onset and age 12 at time of study, Finnish origin

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0000550 (Undetectable electroretinogram), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus), HP:0001312 (Giant somatosensory evoked potentials)

CaseHPOFreeText: Age of onset was 3, while mental decline was present at age 3 and both visual deterioration and giant flash visual evoked potentials at age 6. Abolished ERG was found at age 7, and ataxia at age 8. Seizures and Loss of independent walking occurred at age 9. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant.

ClinVar: 2564 (homozygous)

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant is 0.0008137 (within the European Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77575052-CAT-C

VariantEvidence: NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) is a recurring frameshift variant that is predicted to disrupt approximately 5% of CLN5 at the C-terminus and has been shown to disturb its localization to the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Holmberg_Patient_5, female, age 4 at onset and age 7 at time of study, Finnish origin

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus)

CaseHPOFreeText: Age of onset was 4, while visual deterioration was found at age 6. Mental decline was found at age 7. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant.

ClinVar: 2565 (homozygous)

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant is 0.00005132 (within the European non-Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77566311-G-A

VariantEvidence: NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) is a recurring nonsense variant that is predicted to trigger nonsense-mediated decay of CLN5.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Holmberg_Patient_7, female, age 4 at onset and age 9 at time of study, Finnish origin with some ancestors traced to Sweden

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0000550 (Undetectable electroretinogram), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus), HP:0001312 (Giant somatosensory evoked potentials)

CaseHPOFreeText: Age of onset was 4, while mental decline, visual deterioration and abolished ERG were found at age 7. Ataxia and Seizures developed at age 8, while Loss of independent walking and Giant flash visual evoked potentials occurred at age 9. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.

CaseNotHPOs: HP:0007082 (Dilated third ventricle)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.

Variant: The patient is a compound heterozygote harboring the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) and NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variants.

ClinVar: 2564, 56543

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant is 0.0008137 (within the European Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77575052-CAT-C The maximum allele frequency of the NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variant is 0.00007033 (within the European non-Finnish population, with no homozygotes) https://gnomad.broadinstitute.org/variant/13-77570218-A-AC

VariantEvidence: NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) is a recurring frameshift variant that is predicted to disrupt approximately 5% of CLN5 at the C-terminus and has been shown to disturb its localization to the lysosome (PMID:20052765). NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) is also a frameshift variant, is predicted to disrupt ~51% of the protein product, and exhibits defective localization to the ER rather than the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Holmberg_Patient_3, male, age 3 at onset and age 19 at time of death, Finnish origin

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0000550 (Undetectable electroretinogram), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus), HP:0001312 (Giant somatosensory evoked potentials)

CaseHPOFreeText: Age of onset was 4, while mental decline, visual deterioration and abolished ERG were found at age 6. Giant flash visual evoked potentials were present at age 8, and ataxia at age 9. Seizures and Loss of independent walking occurred at age 10. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant.

ClinVar: 2564 (homozygous)

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant is 0.0008137 (within the European Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77575052-CAT-C

VariantEvidence: NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) is a recurring frameshift variant that is predicted to disrupt approximately 5% of CLN5 at the C-terminus and has been shown to disturb its localization to the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

Case: Saihan_2009_Family_patient_III:4, male, British (of Welsh origin), 47 years old at presentation

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: The mother of the proband and affected siblings was unaffected and negative for the variant, while the father was affected but not genotyped.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0000529 (Progressive visual loss), HP:0000572 (Visual loss), HP:0011510 (Drusen), HP:0031239 (Extrafoveal choroidal neovascularization), HP:0031528 (Subretinal deposits),

CaseHPOFreeText: First presenting phenotypes were reduction of night vision and slow dark adaptation (with onset in fifth decade, 1 year prior to vision loss). Nyctalopia was progressive, with onset in the fifth decade of life (age 47). Vision loss in one eye occurred suddenly at age 48, but had not occurred in the other eye by age 51. Occasional drusen-like deposits were present at the posterior pole. Choroidal neovascularization was hemorrhagic and initiated loss of central vision. A large tear was observed in the retinal pigment epithelium. RPE-choroid complex showed increased reflectivity in both eyes. Left eye had signs of retinal atrophy.

CaseNotHPOs: HP:0004328 (Abnormal anterior eye segment morphology), HP:0000518 (Cataract)

CaseNotHPOFreeText: No history of renal disease or systemic disease was consistently observed among the affected family members. Left eye was largely unaffected at the time of evaluation.

CasePreviousTesting: Family history (indicating autosomal dominant inheritance of retinal degeneration) and ophthalmic exams (including LogMAR visual acuities, slit-lamp biomicroscopy, color fundus photography, optical coherence tomography scans of the fovea, and autofluorescent imaging of the fundus).

GenotypingMethod: Mutational screening of TIMP3 by bidirectional Sanger sequencing

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: The Variant used was NM_000362.5(TIMP3):c.484G>A (p.Glu162Lys) (CAID:CA411540222). The variant is referred to in this publication as "Glu139Lys" (due to the removal of a 23-amino acid N-terminal signal peptide from the polypeptide sequence) but encodes Glu162Lys in the full/updated polypeptide sequence.

CAID: CA411540222

gnomAD: Variant is absent from gnomAD.

VariantEvidence: When the missense variant was exogenously expressed in a retinal epithelial cell line, reverse zymographs of the extracellular matrix revealed the presence of both monomeric and dimeric species for the variant but only the monomeric species for the wild-type. This indicated that the free cysteine present in the variant did not compromise metalloproteinase inhibitory activity, but likely facilitated an intramolecular disfulfide bonding interaction with another TIMP3 molecule. This gain-of-function interpretation of the variant effect would be consistent with the autosomal dominant mechanism of inheritance.

Case: Langton_2000_Family_1_patient_II2, female, country of origin northeast England (PMID:11734514), onset at 25 years of age

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: Variant inherited by the proband rather than acquired de novo, although parents were not genotyped.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0032284 (Ultra-low vision with retained motion projection), HP:0000533 (Chorioretinal atrophy), HP:0007843 (Attenuation of retinal blood vessels), HP:0007703 (Abnormality of retinal pigmentation)

CaseHPOFreeText: Presentation at age 25 was with nyctalopia and loss of central vision. At age of 72, remaining visual acuity was limited to retained motion projection, and chorioretinal atrophy was complete in each macula. Pigmentation was observed in the retinal periphery.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: Rheumatological exam and renal function were both normal.

CasePreviousTesting: Phenotypic characterization only

GenotypingMethod: PCR of TIMP3 exon 5 followed by Sanger sequencing of the PCR product

PreviouslyPublished: PMID:11734514

SupplementalData: N/A

Variant: The NM_000362.5(TIMP3):c.484G>T, p.Glu139X variant converts the GAG codon to a TAG, resulting in early termination of the transcript. This nonsense substitution affects the final exon 5, so that truncation of the protein product is predicted but not nonsense-mediated decay of the transcript.

ClinVar: 12680

gnomAD: Variant is absent from gnomAD.

VariantEvidence: This nonsense variant may result in an unpaired Cys residue (with the potential to mediate dimerization). However, unlike some other variants (missense), this nonsense variant forms dimers that are difficult to distinguish from full-length TIMP3 when exogenously expressed in COS-7 cells (Figure 5). Reverse zymography also indicates retained activity as a metalloproteinase inhibitor. The molecular weight is consistent with the prediction that the premature stop codon removes the C-terminal site for N-glycosylation. This lower molecular weight (unglycosylated) species is unique to the variant and is not seen in the wild-type condition (Fig. 5).

Case#: Marlhens_1997_Patient_III-2, female, age 20 years at time of report, unspecified ethnicity

CasePresentingHPOs: HP:0030506 (Yellow/white lesions of the retina), HP:0000580 (Pigmentary retinopathy), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor), HP:0001141 (Severely reduced visual acuity)

CaseHPOFreeText: Pigmentary deposits, Attenuation of retinal blood vessels, and Optic disc pallor were all mild/moderate.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: All RPE65 coding exons and flanking sequences were PCR-amplified and subjected to single-strand conformation analysis. Exon 10 was identified as a likely candidate to harbor a variant.

CaseMethod1: Sanger sequencing of all 14 exons of RPE65

CaseMethod2: Screening of PCR products using SSCA for the maternal variant and AlwNI restriction digest for the paternal variant

CaseGenotypingMethod: All 14 exons of RPE65 were PCR-amplified and subjected to Sanger sequencing. Screening of PCR products was also performed using SSCA for the maternal variant and AlwNI restriction digest for the paternal variant.

Variant: Affected individuals are compound heterozygous for the NM_000329.3(RPE65):c.1067del (p.Asn356fs) (maternal) and NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) (paternal) variants.

ClinVar: 98821, 13114

gnomAD: The maximum allele frequency for the NM_000329.3(RPE65):c.1067del (p.Asn356fs) variant is 0.00005458 (within the East Asian population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68903930-AT-A The maximum allele frequency for the NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) variant is 0.00008676 (within the Latino / Admixed American population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68905269-G-A

VariantEvidence: The maternal frameshift variant occurs in exon 10 of 14 and is predicted to either trigger NMD or disrupt 33% of the protein product. The paternal nonsense variant occurs in exon 7 of 14 and is predicted to either trigger NMD or truncate 56% of the protein product. Both are likely to be null variants.

CaseAddInfo: The two variants were confirmed to be in trans, and heterozygous carriers were found to be unaffected. Potential parental consanguinity was not mentioned.

CasePMIDs: N/A

FamilyLabel: Marlens_1997_Family_1

FamilyPresentingHPOs: HP:0030506 (Yellow/white lesions of the retina), HP:0000580 (Pigmentary retinopathy), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor), HP:0001141 (Severely reduced visual acuity)

FamilyPresentingHPOFreeText: Pigmentary deposits, Attenuation of retinal blood vessels, and Optic disc pallor were all mild/moderate.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Not specified

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: All RPE65 coding exons and flanking sequences were PCR-amplified and subjected to single-strand conformation analysis. Exon 10 was identified as a likely candidate to harbor a variant. All 14 exons of RPE65 were PCR-amplified and subjected to Sanger sequencing in both affected family members and their parents.

Family#GenotypingMethod: Screening of PCR products from affected and unaffected family members for the variants of interest was performed using SSCA for the maternal variant and AlwNI restriction digest for the paternal variant.

Affected: 2

Unaffected: 1

Segregations: The pedigree (Figure 1c) shows 1 segregation, with none inconsistent.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Marlhens_1997_Patient_III-2

Variant: Affected individuals are compound heterozygous for the NM_000329.3(RPE65):c.1067del (p.Asn356fs) (maternal) and NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) (paternal) variants.

ClinVar: 98821, 13114

gnomAD: The maximum allele frequency for the NM_000329.3(RPE65):c.1067del (p.Asn356fs) variant is 0.00005458 (within the East Asian population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68903930-AT-A The maximum allele frequency for the NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) variant is 0.00008676 (within the Latino / Admixed American population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68905269-G-A

FamilyAddInfo: The two variants were confirmed to be in trans, and heterozygous carriers were found to be unaffected. Potential parental consanguinity was not mentioned.

FamilyPMIDs: N/A

FamilyLabel: Liu_2007_Family

Family#PresentingHPOs: HP:0006934 (Congenital nystagmus), HP:0007750 (Hypoplasia of the fovea), HP:0000483 (Astigmatism), HP:0007663 (Reduced visual acuity)

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with congenital nystagmus segregating with an X-linked mode of inheritance. While all members exhibit nystagmus, some members have foveal hypoplasia (4 out of 5 affected males), myopia, amblyopia, and/or mottling of the retinal pigmentation as well.

FamilyNotHPOs: HP:0001000 (Abnormality of skin pigmentation), HP:0009887 (Abnormality of hair pigmentation), HP:0012805 (Iris transillumination defect), HP:0007894 (Hypopigmentation of the fundus)

FamilyNotHPOFreeText: One family member was subjected to functional MRI and did not show abnormalities of the optic nerve head.

CountryOrigin: China

Ethnicity: Chinese

Race: Not specifically described

Family#PreviousTesting: Linkage mapping has been performed in affected and unaffected family members using 33 polymorphic markers along the entire X chromosome. Haplotype analysis identified a shared region of approximately 10.6 Mb in all affected males.

Family#Method1: Linkage mapping and haplotype analysis

Family#Method2: Sanger sequencing of 21 candidate genes in the linkage region

Family#GenotypingMethod: Linkage mapping has been performed in affected and unaffected family members using 33 polymorphic markers along the entire X chromosome. Haplotype analysis identified a shared region of approximately 10.6 Mb in all affected males. Sanger sequencing was then performed for 21 candidate genes in the linkage region, followed by RFLP analysis in a subset of affected and unaffected family members.

Affected: 4 fully genotyped, 9 total

Unaffected: 7 fully genotyped

Segregations: 8 segregations are shown by the pedigree in Figure 2B.

PublishedLOD: 8.89 (associated with the DXS987 marker on chromosome Xp22)

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Liu_2007_Family_Patient_V-10

Variant: The affected male family members harbor the NM_000273.3(GPR143):c.266C>T (p.Ser89Phe) variant in the hemizygous state.

ClinVar: 10522

gnomAD: This variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_000273.3(GPR143):c.266C>T (p.Ser89Phe) is a missense variant in exon 2 of 9 total, and is located in a transmembrane domain but does not have experimental evidence of gene impact.

FamilyAddInfo: The family is not reported to be consanguineous.

FamilyPMIDs: N/A

Case#: Gu_1997_Family_PMK30_Patient_V-5, male, unknown age, Indian ethnicity

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000505 (Visual impairment), HP:0008047 (Abnormality of the vasculature of the eye), HP:0000648 (Optic atrophy), HP:0007737 (Bone spicule pigmentation of the retina)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing consisted of linkage analysis using microsatellite repeat markers.

CaseMethod1: PCR products were screened by single-strand conformation polymorphism (SSCP) analysis.

CaseMethod2: Sanger sequencing of all RPE65 exons

CaseGenotypingMethod: After discovery of a band shift for exon 10, the patient sample was subjected to PCR and Sanger sequencing of all RPE65 exons.

Variant: Affected individuals are homozygous for the NM_000329.3(RPE65):c.1087C>A (p.Pro363Thr) variant.

ClinVar: 13117 (homozygous)

gnomAD: The maximum allele frequency for the NM_000329.3(RPE65):c.1087C>A (p.Pro363Thr) variant is 0.0001307 (within the South Asian population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68903911-G-T

VariantEvidence: A different publication (PMID: 16828753) later used QBI-293A cells to establish that this variant decreases the stability of the RPE65 protein, shifts its localization from predominantly in the membrane fraction to predominantly in the cytosolic fraction, and abolishes its isomerohydrolase activity.

CaseAddInfo: The family pedigree shows consanguinity in the parents of all affected individuals.

CasePMIDs: N/A

Case#: Gu_1997_Patient_arRP181-II-1, female, 45, German ethnicity

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0000572 (Visual loss), HP:0410280 (Pediatric onset), HP:0000546 (Retinal degeneration), HP:0000618 (Blindness)

CaseHPOFreeText: Visual loss had onset in childhood. Retinal degeneration was diagnosed at age 10. Legal blindness was found at age 18.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing was limited to clinical diagnosis of arRP.

CaseMethod1: PCR amplification and Sanger sequencing

CaseMethod2: N/A

CaseGenotypingMethod: RPE65 was subjected to PCR amplification and Sanger sequencing.

Variant: The patient is homozygous for the NM_000329.3(RPE65):c.11+5G>A variant.

ClinVar: 98825 (homozygous)

gnomAD: The maximum allele frequency of the NM_000329.3(RPE65):c.11+5G>A variant is 0.0001626 (in the European non-Finnish population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68915573-C-T

VariantEvidence: The variant is located within intron 1 of the RPE65 transcript and affects part of the splice donor consensus sequence. SpliceAI calculates a delta score of 0.06 for loss of splice donor site.

CaseAddInfo: Consanguinity of the parents is not proven but considered possible due to their origin from the same village. One of the patient's three siblings is affected (similarly or more severely), but none have been genotyped.

CasePMIDs: N/A

FamilyLabel: Gu_1997_Family_PMK18

FamilyPresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0001098 (Abnormal fundus morphology)

FamilyPresentingHPOFreeText: Onset is early and course of disease is severe. The appearance of the fundus in adulthood is considered characteristic of retinitis pigmentosa.

FamilyNotHPOs: N/A

CountryOrigin: India

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Previous testing consisted of linkage analysis using microsatellite repeat markers (D152803, DJS1665, D1S438 and DJS1728) associated with the RPE65 locus.

Family#Method1: Linkage analysis

Family#GenotypingMethod: PCR products from affected and control family members were screened by restriction digest analysis using the Msel endonuclease.

Affected: 5

Unaffected: 4

Segregations: 7 segregations were reported, with one inconsistent (patient V-8 is heterozygous while the other affected patients are all homozygous). The pedigree (Figure 1) shows consanguinity between the parents of each affected individual.

PublishedLOD: N/A

eLOD: 2.91

AddSegregationInfo: N/A

ProbandLabel: Gu_1997_Family_PMK18_Patient_V-1

Variant: 4 out of 5 affected individuals are homozygous for the variant.

ClinVar: 98893

gnomAD: The NM_000329.3(RPE65):c.858+1G>T variant is not shown in gnomAD.

FamilyAddInfo: The family pedigree shows consanguinity in the parents of all affected individuals.

FamilyPMIDs: N/A

Case#: DiBenedetto_Patient_1, male, age 74 at time of evaluation, Dutch ancestry on maternal (affected) side and North Irish / English on paternal (unaffected) side

CasePresentingHPOs: HP:0000575 (Scotoma), HP:0000662 (Nyctalopia), HP:0000518 (Cataract), HP:0000964 (Eczema), HP:0000822 (Hypertension), HP:0001342 (Cerebral hemorrhage), HP:0001397 (Hepatic steatosis), HP:0009726 (Renal neoplasm), HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0007703 (Abnormality of retinal pigmentation), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007894 (Hypopigmentation of the fundus)

CaseHPOFreeText: Onset in 5th decade of life, anterior chamber intraocular lenses in both eyes (shown by slit lamp examination), bilateral cataract surgery at age 60, stroke at age 71, renal tumor at age 74, visual acuity limited to hand motion at age 74, initial diagnosis not with SFD but with retinitis pigmentosa.

CaseNotHPOs: HP:0012632 (Abnormal intraocular pressure), HP:0025574 (Macular hemorrhage), HP:0030496 (Macular exudate),

CaseNotHPOFreeText: Features of syndromic retinal dystrophy

CasePreviousTesting: Limited (non genome-wide) genetic testing confirming absence of pathogenic variants in 13 different genes; RHO, PRPH2/RDS, RP1, IMPDH1, PRPF31, PRPF, PRPF8, NR2E3, SNRNP200, TOPORS, KLHL7, RPGR, and RP2.

CaseMethod1: Limited genetic testing for 13 candidate genes

CaseMethod2: N/A

CaseGenotypingMethod: next-generation sequencing analysis of an 856-gene retinal dystrophy panel

Variant: NM_000362.5(TIMP3):c.410A>G (p.Tyr137Cys)

CAID: CA411539826

gnomAD: The variant is not found in gnomAD.

VariantEvidence: The variant is a missense substitution at a conserved amino acid. A homology model (based on an available TIMP2 crystal structure) indicates that the variant is a more hydrophobic substitution at a surface-exposed site. This may disrupt protein-protein interactions, particularly with EFEMP1, which is known to interact with the region.

CaseAddInfo: The proband has a number of family members diagnosed with retinitis pigmentosa (son, sister, brother, mother, maternal grandmother, and maternal great-uncle ). The pattern was consistent with autosomal dominant inheritance. His sister underwent treatment for choroidal neovascularization at age 73.

CasePMIDs: N/A

Case#: Yzer_2006_Patient_22018, male, age 2 months at diagnosis, Dutch or Belgian family origin

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0001483 (Eye poking), HP:0002457 (Abnormal head movements), HP:0030553 (Visual acuity no light perception), HP:0000543 (Optic disc pallor), HP:0000639 (Nystagmus), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis. No perception of light was detected at age 2.5 years. Pupils were wide and minimally responsive to bright light.

CaseNotHPOs: HP:0000662 (Nyctalopia), HP:0000613 (Photophobia), HP:0001098 (Abnormal fundus morphology)

CaseNotHPOFreeText: Most recent fundus examination was relatively normal at 3 years of age.

CasePreviousTesting: An LCA-specific microarray ChIP was used for initial genotyping, using antisense oligos to screen for 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK).

CaseMethod1: Sanger sequencing of PCR products from the relevant exon of GUCY2D.

CaseMethod2: N/A

CaseGenotypingMethod: The individual was initially screened using an LCA-specific microarray ChIP with antisense oligos to detect 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK). Subsequent genotyping was performed by Sanger sequencing of PCR products from the relevant exon of the GUCY2D locus.

Variant: The individual is homozygous for the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant.

ClinVar: 98563

gnomAD: The NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant exhibits a maximum allele frequency of 0.0002943 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7917236-C-T

VariantEvidence: Multiple publications have found functional defects in the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant. PMID: 25477517 shows defective binding to its interacting partner RD3, while PMID: 20050595 and PMID: 23035049 show reduced basal enzymatic activity and inability to interact with the activity-stimulating binding partner GCAP1.

CaseAddInfo: Parents were not reported to be consanguineous. Segregation / phasing of two variants was not confirmed by parental genotyping.

CasePMIDs: N/A

Case#: Yzer_2006_Patient_21557, male, age 4 months at diagnosis, Dutch or Belgian family origin

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0000618 (Blindness), HP:0030553 (Visual acuity no light perception), HP:0000563 (Keratoconus), HP:0007688 (Undetectable light- and dark-adapted electroretinogram), HP:0020049 (Exodeviation), HP:0000518 (Cataract), HP:0000639 (Nystagmus),

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis. Bilateral cataracts were dense and prevented fundoscopy.

CaseNotHPOs: HP:0000662 (Nyctalopia), HP:0000613 (Photophobia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: An LCA-specific microarray ChIP was used for initial genotyping, using antisense oligos to screen for 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK).

CaseMethod1: Sanger sequencing of PCR products from the relevant exon of GUCY2D.

CaseMethod2: N/A

CaseGenotypingMethod: The individual was initially screened using an LCA-specific microarray ChIP with antisense oligos to detect 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK). Subsequent genotyping was performed by Sanger sequencing of PCR products from the relevant exon of the GUCY2D locus.

Variant: The individual is homozygous for the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant.

ClinVar: 98563

gnomAD: The NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant exhibits a maximum allele frequency of 0.0002943 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7917236-C-T

VariantEvidence: Multiple publications have found functional defects in the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant. PMID: 25477517 shows defective binding to its interacting partner RD3, while PMID: 20050595 and PMID: 23035049 show reduced basal enzymatic activity and inability to interact with the activity-stimulating binding partner GCAP1.

CaseAddInfo: Parents were note reported to be consanguineous. Segregation / phasing of two variants was confirmed by parental genotyping.

CasePMIDs: N/A

Case#: Narumi_2010_patient_3, male, age 10 years at report, national origin listed as Japanese

CasePresentingHPOs: HP:0000939 (Osteoporosis), HP:0011463 (Childhood onset), HP:0000572 (Visual loss), HP:0000639 (Nystagmus), HP:0000541 (Retinal detachment), HP:0004327 (Abnormal vitreous humor morphology, vascular remnants), HP:0008046 (Abnormal retinal vascular morphology), HP:0000618 (Blindness), HP:0001249 (Intellectual disability), HP:0020110 (Bone fracture), HP:0001388 (Joint laxity), HP:0001252 (Hypotonia), HP:0007083 (Hyperactive patellar reflex), HP:0000938 (Osteopenia), HP:0000926 (Platyspondyly)

CaseHPOFreeText: The patient has been diagnosed with osteoporosis-pseudoglioma syndrome. In one eye, peripheral retinal vessel was insufficiently developed and optic disc traction was observed. Complete blindness occurred at age 3 due to deterioration of abnormal vascular growth in one eye.

CaseNotHPOs: N/A

CaseNotHPOFreeText: No deformity of long bones was observed.

CasePreviousTesting: Genotyping appears to have been limited to the LRP5 locus.

CaseMethod1: Sanger sequencing of 23 PCR-amplified exons and flanking regions of the LRP5 locus

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of 23 PCR-amplified exons and flanking regions of the LRP5 locus.

Variant: The patient harbors the NM_002335.4(LRP5):c.1145C>T (p.Pro382Leu) and NM_002335.4(LRP5):c.4600C>T (p.Arg1534Ter) variants in the compound heterozygous state.

ClinVar: 40288, 40290

gnomAD: The NM_002335.4(LR5P5):c.1145C>T (p.Pro382Leu) variant is found in gnomAD v2.1.1 at a frequency of 0.000008800 (1/113634) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-68153913-C-T The NM_002335.4(LRP5):c.4600C>T (p.Arg1534Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LR5P5):c.1145C>T (p.Pro382Leu) is a missense variant that does not have evidence of impact on the protein product, although it has been observed in the compound heterozygous state in an apparently unrelated proband from this same study. NM_002335.4(LRP5):c.4600C>T (p.Arg1534Ter) is a nonsense variant in exon 23 of 23 and is predicted not to trigger nonsense-mediated decay but rather to truncate the C-terminal 5% of the protein product.

CaseAddInfo: The patient has 2 apparently unaffected parents, one of whom carries the p.Arg1534Ter variant (mother), and one of whom carries the p.Pro382Leu variant (father)

CasePMIDs: N/A

Case#: Narumi_2010_patient_4, male, age 7 years at report, national origin listed as Japanese

CasePresentingHPOs: HP:0000555 (Leukocoria, bilateral), HP:0000541 (Retinal detachment), HP:0007968 (Remnants of the hyaloid vascular system), HP:0000529 (Progressive visual loss), HP:0000618 (Blindness), HP:0001249 (Intellectual disability), HP:0002757 (Recurrent fractures), HP:0000938 (Osteopenia), HP:0000926 (Platyspondyly), HP:0000774 (Narrow chest), HP:0000883 (Thin ribs), HP:0003100 (Slender long bone), HP:0004322 (Short stature), HP:0004349 (Reduced bone mineral density)

CaseHPOFreeText: The patient has been diagnosed with osteoporosis-pseudoglioma syndrome. Minor breathing problems were observed at birth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping appears to have been limited to the LRP5 locus and the surrounding genomic region.

CaseMethod1: Oligonucleotide tiling microarray analyses in the 600-kb region around LRP5.

CaseMethod2: Sanger sequencing of 23 PCR-amplified exons and flanking regions of the LRP5 locus

CaseGenotypingMethod: Genotyping appears to have been limited to oligonucleotide tiling microarray analyses in the 600-kb region around LRP5, and Sanger sequencing of 23 PCR-amplified exons and flanking regions of the LRP5 locus.

Variant: The patient harbors the NM_002335.4(LRP5):c.1584+1G>A and NC_000011.8:g.(67967534_67967551)_(67974756_67974774)del variants in the compound heterozygous state.

ClinVar: 40291, 40292

gnomAD: The NM_002335.4(LRP5):c.1584+1G>A and NC_000011.8:g.(67967534_67967551)_(67974756_67974774)del variants were not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.1584+1G>A is a canonical splice site variant that triggers the inclusion of 63 aberrant base pairs between exons 7 and 8 (Figure 3A). NC_000011.8:g.(67967534_67967551)_(67974756_67974774)del is a 7.2-kb microdeletion that removes the final two exons of LRP5, disrupting the C-terminal 7% of the protein product.

CaseAddInfo: The patient has 2 apparently unaffected parents, one of whom carries the NM_002335.4(LRP5):c.1584+1G>A variant (mother) and one of whom carries the NC_000011.8:g.(67967534_67967551)_(67974756_67974774)del variant (father). Both parents and a carrier sister had significantly decreased bone mineral density, and the father had multiple reported long bone fractures.

CasePMIDs: N/A

Case#: Weisschuh_2018_Patient_8, sex unreported, age 35 years at time of report, likely from Europe or of European descent

CasePresentingHPOs: HP:0030465 (Undetectable light-adapted electroretinogram), HP:0030534 (Abnormal best corrected visual acuity test), HP:0000551 (Color vision defect), HP:0000613 (Photophobia)

CaseHPOFreeText: The proband has been previously diagnosed with achromatopsia.

CaseNotHPOs: HP:0030469 (Abnormal dark-adapted electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The patient was previously genotyped by Sanger sequencing of CNGB3, CNGA3, and GNAT2.

CaseMethod1: next-generation sequencing of PDE6C and possibly other loci

CaseMethod2: screening of the 22 exons and flanking regions of PDE6C (the only strong candidate gene) using Sanger sequencing

CaseGenotypingMethod: The proband has been genotyped by Sanger sequencing of CNGB3, CNGA3, GNAT2, and PDE6C, as well as next-generation sequencing of PDE6C and possibly other loci.

Variant: The proband harbors the NM_006204.4(PDE6C):c.78del (p.Lys27fs) and NM_006204.4(PDE6C):c.775C>T (p.Arg259Ter) variants in the compound heterozygous state.

ClinVar ID: 487693, 487691

gnomAD: The NM_006204.4(PDE6C):c.78del (p.Lys27fs) variant was not found in gnomAD v2.1.1. The NM_006204.4(PDE6C):c.775C>T (p.Arg259Ter) variant is found in gnomAD v2.1.1 at a frequency of 0.00001759 (2/113724) in the European (non-Finnish) population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/10-95381740-C-T

VariantEvidence: NM_006204.4(PDE6C):c.775C>T (p.Arg259Ter) is a nonsense variant in exon 4 of 22 that is predicted to trigger nonsense mediated decay or to at least truncate the C-terminal 70% of the protein product. NM_006204.4(PDE6C):c.78del (p.Lys27fs) is a frameshift variant in exon 1 of 12 that is predicted to trigger nonsense mediated decay or to at least truncate the C-terminal 97% of the protein product.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Weisschuh_2018_Patient_3, sex unreported, age 17 years at time of report, likely from Europe or of European descent

CasePresentingHPOs: HP:0030465 (Undetectable light-adapted electroretinogram), HP:0000613 (Photophobia), HP:0000639 (Nystagmus)

CaseHPOFreeText: The proband has been previously diagnosed with achromatopsia.

CaseNotHPOs: HP:0030469 (Abnormal dark-adapted electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The patient was previously genotyped by Sanger sequencing of CNGB3, CNGA3, and GNAT2.

CaseMethod1: next-generation sequencing of PDE6C and possibly other loci

CaseMethod2: screening of the 22 exons and flanking regions of PDE6C (the only strong candidate gene) using Sanger sequencing

CaseGenotypingMethod: The proband has been genotyped by Sanger sequencing of CNGB3, CNGA3, GNAT2, and PDE6C, as well as next-generation sequencing of PDE6C and possibly other loci.

Variant: The proband harbors the NM_006204.4(PDE6C):c.1579C>T (p.Arg527Ter) variant in the homozygous state.

ClinVar ID: 487692

gnomAD: The NM_006204.4(PDE6C):c.1579C>T (p.Arg527Ter) variant is found in gnomAD v2.1.1 at a frequency of 0.0002603 (9/34574) in the Latino / Admixed-American population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/10-95399923-C-T

VariantEvidence: NM_006204.4(PDE6C):c.1579C>T (p.Arg527Ter) is a nonsense variant in exon 12 of 22 that is predicted to trigger nonsense mediated decay or to at least truncate the C-terminal 39% of the protein product.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Kajiwara_1993_Proband_III-1, male, age 59 years at time of report, family origin not reported

CasePresentingHPOs: Adult onset HP:0003581, Nyctalopia HP:0000662, Reduced visual acuity, HP:0007663, Foveal hyperpigmentation HP:0008001, Foveal atrophy HP:0025010, Subretinal deposits HP:0031528, Uveitis HP:0000554, Cataract HP:0000518, Corneal opacity HP:0007957, Central scotoma HP:0000603, Chorioretinal atrophy HP:0000533, Optic disc pallor HP:0000543

CaseHPOFreeText: The proband has been diagnosed with autosomal dominant retinitis pigmentosa albescens, with age of reported onset after 40 years.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing consisted of screening of the RHO locus for disease-causing variants.

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of PRPH2

CaseGenotypingMethod: Previous testing of this family consisted of screening of the RHO locus for variants causing RP, with negative results. Genotyping started with single strand conformation polymorphism analysis of PCR-amplified products from the PRPH2 gene, followed by Sanger sequencing of the relevant PCR product to identify the variant. SSCP was subsequently performed to genotype family members..

Variant: The proband harbors the NM_000322.5(PRPH2):c.73_74del (p.Trp25fs) variant in the heterozygous state.

ClinVar ID: 98707

gnomAD: The NM_000322.5(PRPH2):c.73_74del (p.Trp25fs) variant was not found in gnomAD v4.0.0.

VariantEvidence: NM_000322.5(PRPH2):c.73_74del (p.Trp25fs) is a frameshift variant in exon 1 of 3 that is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 93% of the protein product.

CaseAddInfo: The proband's family includes a daughter who is an "unaffected" (subclinically affected) carrier of the variant with an elevated dark-adapted threshold and numerous yellow/white subretinal flecks in the periphery of the fundus with macular sparing.

CasePMIDs: N/A