PMID: 23160995

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

Case#: Bravo-Gil_2016_Proband_488, sex not specified, onset at birth, family origin reported as Spanish

CasePresentingHPOs: HP:0000618 (Blindness), HP:0001133 (Constriction of peripheral visual field), and HP:0000662 (Nyctalopia), HP:0003577 (Congenital onset), HP:0000639 (Nystagmus), HP:0010442 (Polydactyly). HP:0001249 (Intellectual disability), HP:0001513 (Obesity)

CaseHPOFreeText: The proband is part of an inherited retinal disease cohort and received an initial diagnosis of Bardet-Biedl syndrome. Reduced visual acuity was the first visual symptom. The patient is now described as having total blindness.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was genotyped by a capture-based next-generation sequencing panel that included 64 known retinal genes.

CaseMethod1: next-generation sequencing panel

CaseMethod2: Sanger sequencing of BBS1 to validate the presence of the variants

CaseGenotypingMethod: The proband was genotyped by a capture-based next-generation sequencing panel that included 64 known retinal genes, followed by Sanger sequencing of BBS1 to validate the presence of the variants.

Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) and NM_024649.5(BBS1):c.118del (p.Cys40fs) variants in the compound heterozygous state.

ClinVar ID: 12143, 802688

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.118del (p.Cys40fs) variant is found in gnomAD v2.1.1 at a frequency of 0.00005782 (2 alleles / 34592 total alleles, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/11-66278553-CT-C?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. NM_024649.5(BBS1):c.118del (p.Cys40fs) is a frameshift variant in exon 2 of 17 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 has not been described as consanguineous.

CasePMIDs: N/A

Case#: Bravo-Gil_2016_Proband_95, sex not specified, age 7 years at onset, family origin reported as Spanish

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0001133 (Constriction of peripheral visual field), and HP:0000662 (Nyctalopia), HP:0000550 (Undetectable electroretinogram), HP:0410280 (Pediatric onset)

CaseHPOFreeText: The proband is part of an inherited retinal disease cohort and received an initial diagnosis of simplex retinitis pigmentosa. Night blindness was the first visual symptom.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was genotyped by a capture-based next-generation sequencing panel that included 64 known retinal genes.

CaseMethod1: next-generation sequencing panel

CaseMethod2: Sanger sequencing of BBS1 to validate the presence of the variants

CaseGenotypingMethod: The proband was genotyped by a capture-based next-generation sequencing panel that included 64 known retinal genes, followed by Sanger sequencing of BBS1 to validate the presence of the variants.

Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) and NM_024649.5(BBS1):c.1474-2A>G variants in the compound heterozygous state.

ClinVar ID: 12143

CAID: CA381424925

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.1474-2A>G variant 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.1474-2A>G is a canonical splice site variant in intron 14 that is predicted but not confirmed to disrupt BBS1 splicing.

CaseAddInfo: The proband's family has not been described as consanguineous.

CasePMIDs: N/A

Case#: Solmaz_2015_Proband_9, male, age 19 years at time of report, part of cohort from Turkey

CasePresentingHPOs: HP:0031418 (Increased body mass index), HP:0000510 (Rod-cone dystrophy), HP:0000750 (Delayed speech and language development), HP:0000218 (High palate), HP:0000678 IDental crowding), HP:0010442 (Polydactyly), HP:0001159 (Syndactyly), HP:0001156 (Brachydactyly), HP:0000026 (Male hypogonadism), HP:0001256 (Intellectual disability, mild)

CaseHPOFreeText: The patient has been diagnosed with Bardet-Biedl syndrome.

CaseNotHPOs: HP:0000365 (Hearing impairment), HP:0000077 (Abnormality of the kidney)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of an NGS-based panel focusing on the BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, CEP290, WDPCP, SDCCAG8, NPHP1 loci.

CaseMethod1: NGS-based panel focusing on the BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, CEP290, WDPCP, SDCCAG8, NPHP1 loci.

CaseMethod2: Sanger sequencing of the BBS7 locus

CaseGenotypingMethod: Genotyping consisted of an NGS-based panel focusing on the BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, CEP290, WDPCP, SDCCAG8, NPHP1 loci, followed by Sanger sequencing of the BBS7 locus.

Variant: The patient harbors the NM_018190.4:c.712_715del (p.Arg238GlufsTer59) variant in the homozygous state.

CAID: CA3064432

gnomAD: The NM_018190.4:c.712_715del (p.Arg238GlufsTer59) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.0001146 (13/113390) in the European non-Finnish population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/4-122775861-CCTCT-C

VariantEvidence: NM_018190.4:c.712_715del (p.Arg238GlufsTer59) is an out-of-frame deletion variant in exon 7 of 18 and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 65% of the protein product.

CaseAddInfo: Consanguinity of this specific patient's family is unknown, but the cohort was reported to have a high rate of consanguineous probands.

CasePMIDs: N/A

PMID: 26518167

Gene: BBS7

HGNC: 18758

Disease: Bardet-Biedl syndrome 7

MONDO: 0014435

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS7 variants among Bardet-Biedl syndrome cohorts has been reported at 4.2% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.

ExperimentName: Colorblind squirrel monkeys were rescued by human OPN1LW.

NonHumanModel: Saimiri sciureus

GeneAlteration: Male squirrel monkeys were missing OPN1LW gene. Controls with the intact gene were not part of the study.

RescueVariant: Rescue was performed by subretinal injection of recombinant adeno-associated virus containing human OPN1LW under control of the appropriate enhancer and promoter and featured the wild-type gene rather than a variant.

RescuePhenotype: The rescued phenotypes are inability to discriminate between blue and green wavelengths to obtain a food reward and defects in performance on a computer-administered Cambridge colour test.

RescueMethod: This rescue model has injection of recombinant adeno-associated virus containing human wild-type OPN1LW under control of the appropriate enhancer and promoter.

RescueEvidence: Squirrel monkeys gained the ability to discriminate between blue and green wavelengths to obtain a food reward (data not shown), as well as significant improvement in ability to distinguish colors occurring at ~20 weeks post-injection (Figure 3A). Gaps in the ability to detect certain wavelengths pre-injection (solid lines) were filled in post-injection (dotted lines) in monkey 1 (Panel 3B) and monkey 2 (Panel 3C). These confirmed that monkeys had become trichomatic and matched the new ability to access food rewards.

ModelVariant: The model does not include any human OPN1LW variant, only the wild-type gene.

Selection A- Gene with same function implicated in disease

ExperimentName: PRPF4 is a U4/U6 small nuclear ribonucleoprotein component that functions in mRNA splicing.

GOterm: GO:0000398 (mRNA splicing, via spliceosome)

FunctionalEvidence: PRPF4, PRPF3, PRPF31, and PRPF8 are all splicing factors involved in mRNA processing and are encoded by genes that harbor variants associated with retinitis pigmentosa.

HGNC: HGNC:17348 (PRPF3, retinitis pigmentosa 18), HGNC:15446 (PRPF31, retinitis pigmentosa 11), HGNC:17340 (PRPF8, retinitis pigmentosa 13)

GeneEvidence: PRPF3 harbors variants that cause retinitis pigmentosa 18 (PMID: 11773002), PRPF31 harbors variants that cause retinitis pigmentosa 11 (PMID: 12444105), and PRPF8 harbors variants that cause retinitis pigmentosa 13 (PMID: 7951236).

SharedGeneImplication: PRPF4, PRPF3, PRPF31, and PRPF8 are encode splicing factors involved in mRNA processing.

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.

PMID: 33691693

Gene: TOPORS

Case#: Gal_2011_Family_5_Proband_P9, female, age 21 years at time of report, family national origin described as Saudi

CasePresentingHPOs: Hypermetropia HP:0000540, Microphthalmia HP:0000568

CaseHPOFreeText: The proband received a diagnosis of posterior microphthalmos, with one feature being a moderate papillomacular fold.

CaseNotHPOs: Ocular hypertension HP:0007906

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband's family may have been previously subjected to linkage mapping, and was also previously genotyped by Sanger sequencing of the MFRP locus.

CaseMethod1: Sanger sequencing of MFRP

CaseMethod2: Sanger sequencing of PRSS56

CaseGenotypingMethod: The proband's family may have been previously subjected to linkage mapping, and was also previously genotyped by Sanger sequencing of the MFRP locus, followed by Sanger sequencing of PRSS56.

Variant: The individual harbors the NM_001195129.2(PRSS56):c.1066dup (p.Gln356fs) variant in the homozygous state.

ClinVar: 31077

gnomAD: This variant is found in gnomAD v4.1.0 at a frequency of 0.0008496 in the Middle Eastern population https://gnomad.broadinstitute.org/variant/2-232523817-A-AC?dataset=gnomad_r4

VariantEvidence: NM_001195129.2(PRSS56):c.1066dup (p.Gln356fs) is a frameshift variant in exon 9 of 13 and is predicted to trigger nonsense-mediated decay.

CaseAddInfo: The proband is from a cohort where more than half of the families had known consanguinity.

CasePMIDs: N/A

PMID: 16116091

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age

Case#: Schmidts_2013_Patient_JATD1, male, 12 years of age at time of study, of Serbian ethnicity

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0002093 (Respiratory insufficiency), HP:0000556 (Retinal dystrophy), HP:0009370 (Type A brachydactyly), HP:0004322 (Short stature), HP:0005257 (Thoracic hypoplasia), HP:0010579 (Cone-shaped epiphysis), HP:0000369 (Low-set ears), HP:0003774 (Stage 5 chronic kidney disease), HP:0007703 (Abnormality of retinal pigmentation), HP:0000803 (Renal cortical cysts), HP:0033130 (Abnormal renal echogenicity), HP:0000822 (Hypertension), HP:0000773 (Short ribs), HP:0000900 (Thickened ribs), HP:0000774 (Narrow chest)

CaseHPOFreeText: This proband was diagnosed with Jeune's asphyxiating thoracic dystrophy (JATD).

CaseNotHPOs: HP:0010442 (Polydactyly), HP:0001737 (Pancreatic cysts), HP:0001392 (Abnormality of the liver), HP:0001263 (Global developmental delay)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing appears to have been limited to a clinical diagnosis of Jeune's asphyxiating thoracic dystrophy.

CaseMethod1: Whole exome sequencing, focusing on variants consistent with autosomal recessive inheritance and homologous to genes present in the ciliary proteome.

CaseMethod2: Sanger sequencing of IFT140 in the patient and available family members

CaseGenotypingMethod: The patient and family members were genotyped by whole exome sequencing and confirmed by Sanger sequencing of IFT140.

Variant: The patient is a compound heterozygote harboring the paternal NM_014714.4(IFT140):c.874G>A (p.Val292Met) and maternal NM_014714.4(IFT140):c.1380del (p.Asn460fs) variants in IFT140.

ClinVar ID: 97053, 97055

gnomAD: The NM_014714.4(IFT140):c.874G>A (p.Val292Met) variant is present in gnomAD at a frequency of 0.000008852 in the European non-Finnish population (1/112966, with no homozygotes). https://gnomad.broadinstitute.org/variant/16-1637962-C-T The NM_014714.4(IFT140):c.1380del (p.Asn460fs) variant is present in gnomAD at a frequency of 0.000008804 in the European non-Finnish population (1/113590, with no homozygotes). https://gnomad.broadinstitute.org/variant/16-1633366-CG-C

VariantEvidence: NM_014714.4(IFT140):c.874G>A (p.Val292Met) is a missense variant that does not have functional evidence of gene impact. NM_014714.4(IFT140):c.1380del (p.Asn460fs) is a frameshift variant that introduces a premature stop codon in exon 12/31 and is predicted to trigger NMD or at least to truncate ~69% of the protein product.

CaseAddInfo: The proband's parents are each heterozygous for one variant.

CasePMIDs: N/A

PMID: 16828753

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 20

MONDO: 0013425

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.

Penetrance: Fully penetrant, with onset typically in childhood

FamilyName: Selmer_Family

FamilyPresentingHPOFreeText: autosomal dominant pericentral retinal dystrophy (adPRD). Sixteen individuals (aged 23–78 years) were ophthalmologically examined as part of this project and 10 of them were assigned a diagnosis of PRD (Table 1). The ophthalmological examinations revealed an atypical form of retinitis pigmentosa (RP), which we prefer to call adPRD. Compared with classical RP, this phenotype has a favourable prognosis

CountryOrigin: Norway

FamilyPreviousTesting: We performed a genome-wide linkage analysis followed by sequencing of a candidate gene to identify the mutation causing the disease.

FamilyMethod1:

FamilyMethod2:

FamilyGenotypingMethod: Mutations in the RHO, RP1, RDS and IMPDH1 genes as a cause of adRP in this family were excluded in a separate study published elsewhere (Grøndahl et al. 2007). Genotyping was performed using the Affymetrix GeneChip® Human Mapping 10 K 2.0 array (Matsuzaki et al. 2004), according to the supplier’s protocol. All three exons of the TOPORS gene, including exon–intron boundaries, were sequenced.

Affected:

Unaffected:

Segregations:

PublishedLOD: 7.3

AddSegregationInfo: Preliminary results of linkage analysis showed a linkage peak with a LOD (logarithm of the odds) score of 2.6 covering the recently reported adRP gene TOPORS. This gene was sequenced in 19 family members and a missense mutation c.1205a>c was identified in exon 3 in all affected members, leading to a p.Q402P amino acid substitution. The mutation showed complete co-segregation with the disease (Fig. 1) in all members tested, and linkage analysis yielded a LOD score of 7.3, assuming complete penetrance and a mutation frequency of 0.001.

ProbandLabel: Selmer_Proband

Variant:

gnomAD: absent in gnomAD

CAID: CA373170940

PMID: 19183411

Gene: TOPORS

PMID: 8634705

Gene: GPR143

HGNC: 20145

Disease: X-linked recessive ocular albinism

MONDO: 0021019

InheritancePattern: X-linked recessive

Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)

Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.

Case: Patient 1

CasePresentingHPOsFreeText: A diagnosis of CSNB1 or CSNB2 was based on standard ERGs. The photopic ERG was the most specific criterion to distinguish between CSNB1 and CSNB2 because it showed a “square-wave” appearance in CSNB1 and a decreased b-wave in CSNB2. Patients with CSNB2 had rod- and cone-related problems. reduced visual acuity, nystagmus, symptoms of night blindness, or high refractive error at a young age.

CasePreviousTesting:

CaseGenotypingMethod: Molecular analysis was performed by direct Sanger sequencing of the entire coding regions in CACNA1F and CABP4 in patients with CSNB2. The coding exons and flanking intron sequences of the different CSNB2 genes were amplified by standardized polymerase chain reaction.

Variant: c.1075G>A (p.Gly359Arg)

ClinVarID: or CAID: CA412919833

gnomAD: variant not present in gnomAD v2.1.1

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

Case: Patient 5

CasePresentingHPOsFreeText: A diagnosis of CSNB1 or CSNB2 was based on standard ERGs. The photopic ERG was the most specific criterion to distinguish between CSNB1 and CSNB2 because it showed a “square-wave” appearance in CSNB1 and a decreased b-wave in CSNB2. Patients with CSNB2 had rod- and cone-related problems. reduced visual acuity, nystagmus, symptoms of night blindness, or high refractive error at a young age.

CasePreviousTesting:

CaseGenotypingMethod: Molecular analysis was performed by direct Sanger sequencing of the entire coding regions in CACNA1F and CABP4 in patients with CSNB2. The coding exons and flanking intron sequences of the different CSNB2 genes were amplified by standardized polymerase chain reaction.

Variant: 1684+1G>A

ClinVarID: or CAID: CA412915988

gnomAD: variant not present in gnomAD v2.1.1

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

Case#: Haider_2000_Proband_6, sex, age, and origin not reported

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

Variant: The individual harbors the NM_014249.4(NR2E3):c.310C>T (p.Arg104Trp) variant in the homozygous state.

ClinVarID: 846973

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.00002739 (2 alleles / 73,032 total alleles) in the African / African-American population, with no homozygous occurrences. https://gnomad.broadinstitute.org/variant/chr15-71811830-C-T?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.310C>T (p.Arg104Trp) is a missense variant within the zinc finger / DNA-binding domain of NR2E3,.

CaseAddInfo: It is not clear whether or not the proband comes from a consanguineous family.

CasePMIDs: N/A

Case#: Haider_2000_Proband_1, male, age and origin not reported

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

Variant: The individual harbors the NM_014249.4(NR2E3):c.119-2A>C variant in the homozygous state.

ClinVarID: 191059

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.001359 in the Ashkenazi Jewish population and 0.0007992 in the European (non-Finnish) population (919 / 1,149,942), with no homozygotes observed. https://gnomad.broadinstitute.org/variant/chr15-71811481-A-C?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.119-2A>C is a canonical splice acceptor site variant adjacent to exon 2 of 6, which is an out-of-frame exon that could potentially trigger nonsense-mediated decay if skipped.

CaseAddInfo: The proband is the offspring of 3rd cousins and has an affected sibling and an affected second cousin once removed harboring the variant in the same homozygous genotype (Figure 3c).

CasePMIDs: N/A

Case#: Haider_2000_Proband_3, sex, age, and origin not reported

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

Variant: The individual harbors the NM_014249.4(NR2E3):c.226C>T (p.Arg76Trp) variant in the homozygous state.

ClinVarID: 5529

gnomAD: The variant is not found in gnomAD version 4.1.0 at a frequency of 0.0001124 in the South Asian population (10 alleles / 88,960 total alleles, with no homozygotes) https://gnomad.broadinstitute.org/variant/chr15-71811590-C-T?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.226C>T (p.Arg76Trp) is a missense variant within the zinc finger / DNA-binding domain of NR2E3, and occurs at the same amino acid position as another missense substitution reported in the same article.

CaseAddInfo: It is not clear whether the proband came from a consanguineous family.

CasePMIDs: N/A

PRPF4, PRPF3, PRPF31, and PRPF8 are all splicing factors involved in mRNA processing and are encoded by genes that harbor variants associated with retinitis pigmentosa.

Case#: Jespersgaard_2019_Patient_163, gender and age not specified, origin likely to be Danish based on cohort

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, as part of a larger group of generalized non-syndromic retinal dystrophies. Detailed phenotypes are not described.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Next-generation sequencing was performed focusing on a targeted panel of 125 genes known to be linked to inherited retinal disease.

CaseMethod1: NGS panel

CaseMethod2: N/A

CaseGenotypingMethod: Next-generation sequencing was performed focusing on a targeted panel of 125 genes known to be linked to inherited retinal disease. It is not clear whether Sanger sequencing was used to validate the genotyping of this particular case.

Variant: The proband harbors the NM_000440.3(PDE6A):c.612del (p.Lys205fs) variant in the homozygous state.

ClinVar: 636056

gnomAD: The NM_000440.3(PDE6A):c.612del (p.Lys205fs) variant is not found in gnomAD v2.1.1.

VariantEvidence: NM_000440.3(PDE6A):c.612del (p.Lys205fs) is a frameshift variant in exon 2 that is predicted to result in nonsense-mediated decay or at least to truncate the C-terminal ~76% of the protein product.

CaseAddInfo: N/A

CasePMIDs: N/A

PMID: 9326941

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 20

MONDO: 0013425

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.

Penetrance: Fully penetrant, with onset typically in childhood

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

ExperimentName: Transgenic mouse expressing human GUCY2D R838S

NonHumanModel: Mus musculus

GeneAlteration: A human GUCY2D transgene encoding the R838S substitution was placed under the control of the rod opsin promoter and injected into mouse eggs, creating a mouse model with rod-specific expression of the variant (and only inefficient expression in cones).

ModelPhenotype: HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0030478 (Abnormal amplitude of dark-adapted bright flash electroretinogram), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0410280 (Pediatric onset), HP:0000546 (Retinal degeneration)

HumanPhenotype: 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)

ModelEvidence: The model system approximately recapitulates the mode of inheritance (autosomal dominant) of the human disease state. At the molecular level, it increases the sensitivity of cGMP synthesis to calcium ion concentration (Figures 2B, 7A). At the ocular level, rod response (dark-adapted ERG) amplitudes were diminished starting at one month of age (Figure 4A, 4B), particularly by 6 months (Figure 5A, 5B), while cones lacking transgene expression remained functional (Figure 5A, 5C). Retinal morphology between 3 and 5 months of age showed outer nuclear layer reduction (Figures 6A, 7C) linked to photoreceptor loss (Figures 6B, 7D).

ModelVariant: NM_000180.4(GUCY2D):c.2512C>A (p.Arg838Ser) (ClinVar: 98568)

FamilyLabel: van_Huet_2014_Family_F, family national origin reported as from Pakistan

Family#PresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina)

FamilyHPOFreeText: The patient and family members have been diagnosed with retinitis pigmentosa, with macular abnormalities present in all cases.

Family#PresentingNotHPOs: N/A

CountryOrigin: Pakistan

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Previous genotyping outside of the IMPG2 locus has not been described for this family.

Family#Method1: Sanger sequencing of the 19 exons of the IMPG2 gene

Family#Method2: N/A

Family#GenotypingMethod: Genotyping may have been limited to Sanger sequencing of the 19 exons of the IMPG2 gene, as previous genotyping of other loci has not been described for this family.

Affected: 3

Unaffected: 3

Segregations: Two segregations are reported in the family, with none inconsistent. The family is apparently consanguineous, with the parents being first cousins. The pedigree is shown in Figure 1.

PublishedLOD: N/A

eLOD: 1.50

AddSegregationInfo: N/A

ProbandLabel: van_Huet_2014_Patient_F-II:2

Variant: The affected family members harbor the NM_016247.4(IMPG2):c.1680T>A (p.Tyr560Ter) variant in the homozygous state.

ClinVar: 437938

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

FamilyAddInfo: The family is reportedly consanguineous, with the parents being first cousins.

FamilyPMIDs: N/A

Case#: van_Huet_2014_Patient_A-II:1, female, age 8 years at the time of onset, age 59 at the time of report, national origin reported as Dutch

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0000545 (Myopia), HP:0000550 (Undetectable electroretinogram), HP:0007787 (Posterior subcapsular cataract), HP:0011504 (Bull's eye maculopathy), HP:0500087 (Peripapillary atrophy), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007722 (Retinal pigment epithelial atrophy), HP:0007737 (Bone spicule pigmentation of the retina)

CaseHPOFreeText: The patient and her family members have been diagnosed with retinitis pigmentosa, with macular abnormalities present in all cases.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping outside of the IMPG2 locus has not been described for this family.

CaseMethod1: Sanger sequencing of the 19 exons of the IMPG2 gene

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping may have been limited to Sanger sequencing of the 19 exons of the IMPG2 gene, as previous genotyping of other loci has not been described for this family.

Variant: The affected family members harbor the NM_016247.4(IMPG2):c.887+430_908+274del variant in the homozygous state.

ClinVar: 3547

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

VariantEvidence: The NM_016247.4(IMPG2):c.887+430_908+274del variant is a deletion of exon 9 that is predicted to lead to in-frame removal of a region encoding 7 amino acids. When expressed exogenously in COS-1 cells, this results in retention of the protein product in the endoplasmic reticulum and failure to properly localize to the plasma membrane (PMID: 20673862, Figure 4).

CaseAddInfo: Despite the homozygous state of the variant, the family is reportedly not consanguineous. The proband has two affected siblings who share the same genotype, and each parent is a heterozygous carrier.

CasePMIDs: PMID: 20673862

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

PMID: 10953198

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

PMID: 8634721

Gene: TIMP3

HGNC: 11822

Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy

MONDO: 0007640

InheritancePattern: Autosomal Dominant

Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)

Penetrance: Fully penetrant, onset between the third and sixth decades of life

ExperimentName: Genotyping of 4 Australian Cattle Dogs affected with NCL

NonHumanModel: Canis familiaris

GeneAlteration: While the model does not have an engineered gene alteration, all four affected animals are homozygous for the CLN5:c.619C>T variant. The unaffected parents of a fifth affected dog were both heterozygotes for this variant.

ModelPhenotype: HP:0001250 (Seizure), HP:0000572 (Visual loss), HP:0000708 (Behavioral abnormality), HP:0002370 (Poor coordination), HP:0002312 (Clumsiness), HP:0001251 (Ataxia), HP:0100299 (Muscle fiber inclusion bodies), HP:0002283 (Global brain atrophy), HP:0002119 (Ventriculomegaly), Note: inclusion bodies are membrane-associated and autofluorescent. Onset of phenotypes was between 12-18 months, and the condition was rapidly progressive, with euthanasia occurring between 20-27 months of age.

HumanPhenotype: 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:0100952 (Enlarged sylvian cistern), HP:0002059 (Cerebral atrophy), HP:0001272 (Cerebellar atrophy)

ModelEvidence: The model phenotypes closely match the human patient phenotypes in the timing of onset and rapid progression (Table 3), neurological details, vision problems, loss of coordination, and microscopic accumulation of storage/inclusion bodies (Figure 4, Figure 5).

ModelVariant: CLN5:c.619C>T p.Gln207Ter

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#: Savukoski_European_Patient_1, no demographic details, Dutch origin

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: PCR products from the four exons of CLN5 were generated from the affected individual and a control individual and subjected to Sanger sequencing. Genome-wide analysis methods were not used.

Variant: Patient is homozygous for NM_006493.4(CLN5):c.688G>A (p.Asp230Asn), although this variant is referred to in the article as c.G2127A or p.Asp279Asn.

ClinVar: 2566

gnomAD: The variant is reported to have a maximum allele frequency of 0.00005437 (in the East Asian population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77574715-G-A

VariantEvidence: This missense variant in the fourth / final exon is predicted to introduce an additional N-glycosylation site within the C-terminal region of CLN5. Slower electrophoretic migration of the exogenously expressed protein indicates that the abnormal N-glycosylation site is functional (PMID:20052765). The variant also disturbs lysosomal trafficking (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

PMID: 9662406

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

PMID: 12552567

Gene: GUCY2D

HGNC: 4689

Disease: Cone-rod dystrophy 6

MONDO: 0011143

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of cone-rod dystrophy is between 1 in 30,000 and 1 in 40,000 (PMID: 17270046), while the proportion of cone-rod dystrophy caused by GUCY2D variants is between 19% and 23% (PMID: 22183351, PMID: 25515582). Thus, the prevalence of cone-rod dystrophy 6 is between 1 in 130,000 and 1 in 215,000.

Penetrance: Penetrance is age-dependent, with onset between the 1st and 6th decades of life.

ExperimentName: Recombinase-based variant knock-in to the mouse Rpe65 locus

NonHumanModel: Mus musculus

GeneAlteration: A substitution equivalent to the human NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was knocked into the mouse Rpe65 locus by Flp-recombinase, which allowed the selection cassette to be subsequently excised.

ModelPhenotype: HP:0030602 (Abnormal fundus autofluorescence imaging), HP:0030329 (Retinal thinning), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0008275 (Abnormal light-adapted electroretinogram)

HumanPhenotype: HP:0000662 (Nyctalopia), HP:0007688 (Undetectable light- and dark-adapted electroretinogram), HP:0001098 (Abnormal fundus morphology), HP:0000529 (Progressive visual loss)

ModelEvidence: The mice exhibit reduced levels of RPE65 protein (Figure 3A) and enhanced ubiquitination (Figure 3B), indicating higher susceptibility to proteolysis. Despite normal 11-cis retinal levels (Figure 7C), the heterozygous knock-in animals exhibit abnormal accumulation of retinyl esters (Figure 7B), recapitulating a key molecular defect of the human patients. Photobleaching revealed defects in regeneration of 11-cis-retinal (Figure 7F) and accumulation of retinyl esters (Figure 7G). These defects were observable in both the heterozygous knock-in (mild) and homozygous knock-in (more severe). Accumulation of autofluorescent spots in the fundus (Figure 4), progressive thinning of the outer nuclear layer (Figure 5), and abnormal ERG responses (Figure 6) were seen in heterozygous knock-in and especially homozygous knock-in mice with age. Similar phenotypic results were observed with a third, similar knock-in mouse model (PMID: 28041994).

ModelVariant: The model knocks the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant (ClinVar:750796) into the endogenous mouse Rpe65 locus.

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.

PMID: 9760202

Gene: TIMP3

HGNC: 11822

Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy

MONDO: 0007640

InheritancePattern: Autosomal Dominant

Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)

Penetrance: Fully penetrant, onset between the third and sixth decades of life

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.

PMID: 10750831

Gene: RBP3

HGNC: 9921

Disease: retinitis pigmentosa 66

MONDO: 0014093

InheritancePattern: autosomal recessive

Prevalence: RBP3-related cases are believed to be very rare (possibly with estimated prevalence of less than 1 in 1,000,000), however, it is believed that there may be under-diagnosis (PMID: 37806543).

Penetrance: RBP3 disease-causing variants appear to have complete penetrance.

Case#: Manes_2013_Family_NAX1_Proband_II:2, female, age unreported, national origin reported as French

CasePresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0032037 (Mildly reduced visual acuity), HP:0030469 (Abnormal dark-adapted electroretinogram, specifically reduced)

CaseHPOFreeText: The patient has been diagnosed with vitelliform macular dystrophy.

CaseNotHPOs: HP:0008179 (Decreased Arden ratio of electrooculogram), HP:0008275 (Abnormal light-adapted electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing appears to have been limited to Sanger sequencing-based screening of exon 7 of IMPG1.

CaseMethod1: Sanger sequencing of the 17 exons and flanking intronic sequences

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping appears to have included Sanger-based sequencing of the 17 exons and intronic flanking sequences of the IMPG1 locus.

Variant: The proband harbors the NM_001563.4(IMPG1):c.1824+1G>A variant in the heterozygous state.

ClinVar: 1240018

gnomAD: The NM_001563.4(IMPG1):c.1824+1G>A variant was found in gnomAD v2.1.1 at a frequency of 0.00002980 (1/33554) in the Latino / Admixed American population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76660278-C-T?dataset=gnomad_r2_1

VariantEvidence: NM_001563.4(IMPG1):c.1824+1G>A is a canonical splice site variant in intron 13 that does not have evidence confirming an impact on the gene product, however, it has been reported by the same researchers in a proband with retinitis pigmentosa (PMID: 32817297).

CaseAddInfo: The proband has two unaffected sisters and an unaffected mother who share the same genotype. Consanguinity is not reported in this family. It is possible that the proband harbors a second unidentified variant in trans, inherited from the father.

CasePMIDs: 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

PMID: 9501220

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age

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

PMID: 11162558

Gene: ADAM9

HGNC: 216

Disease: cone-rod dystrophy 9

MONDO: MONDO:0013002

InheritancePattern: autosomal recessive

Prevalence: The prevalence of cone-rod dystrophy in general is estimated to be 1 in 40,000 (PMID: 17270046), however, the specific prevalence of cone-rod dystrophy 9 is unknown.

Penetrance: Penetrance appears to be complete in reported families, but it is possible that incomplete penetrance may be associated with some variants.

Case#: Kannabiran _2012_Proband_B-2, male, age 10 years at time of report, national origin from India

CasePresentingHPOs: Nyctalopia HP:0000662, Childhood onset HP:0011463, Retinal flecks HP:0012045, Decreased light- and dark-adapted electroretinogram amplitude (rod-cone pattern) HP:0000654, Retinal pigment epithelial atrophy HP:0007722

CaseHPOFreeText: The proband has a diagnosis of autosomal recessive retinitis pigmentosa, with phenotypes highly suggestive of enhanced S-cone syndrome. The proband had gliotic scars in the posterior pole. No OCT was performed, so it is unknown whether macula schisis was present.

CaseNotHPOs: Abnormal optic disc morphology HP:0012795, Abnormal retinal artery morphology HP:0000630, Bone spicule pigmentation of the retina HP:0007737

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of homozygosity mapping, which established linkage to a 41Mb region of chromosome 15, identifying NR2E3 and RLBP1 as the likely candidate loci.

CaseMethod1: Homozygosity mapping within the family of the proband

CaseMethod2: Sanger sequencing of NR2E3 and RLBP1

CaseGenotypingMethod: Genotyping was performed by homozygosity mapping within the family of the proband, followed by Sanger sequencing of NR2E3 and RLBP1.

Variant: The individual harbors the NM_014249.4(NR2E3):c.143_144delinsAGTGTGCCTCCAGTGCCTCGCTCCA (p.Arg48fs) variant in the homozygous state.

ClinVarID: 183143

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

VariantEvidence: NM_014249.4(NR2E3):c.143_144delinsAGTGTGCCTCCAGTGCCTCGCTCCA (p.Arg48fs) is a frameshift variant in exon 2 of 8 that is predicted to introduce a premature stop codon and trigger nonsense-mediated decay.

CaseAddInfo: The proband has two unaffected heterozygous parents and an affected sister who shares the same homozygous genotype.

CasePMIDs: N/A

Selection A- Gene is expressed in tissues relevant to disease:

ExperimentName: Immunohistochemical localization of TIMP3 expression to Bruch's membrane and drusen deposits

TissueExpression: Strong expression was observed in Bruch's membrane (UBERON:0003957) and associated drusen, while weak expression was observed in retinal blood vessels (UBERON:0003501).

ExpressionEvidence: TIMP3 was detected in human eye sections (from patients aged 24 to 85 years) using a monoclonal antibody and a TIMP-3 synthetic peptide for specificity. Bruch's membrane was specifically labeled by the antibody (Figure 2B), with strong labeling observed from the RPE to the elastin sublayer. Drusen associated with Bruch's membrane (particularly smaller deposits) also stained strongly for TIMP3 (Figure 2D), while retinal blood vessels showed weak staining as well. Overall, staining was particularly intense in sections from older patients.

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

PMID: 29522070

Gene: TRPM1

HGNC: 7146

Disease: congenital stationary night blindness 1C

MONDO: MONDO:0013183

InheritancePattern: autosomal recessive

Prevalence: Congenital stationary night blindness has an estimated prevalence between 1 in 6,000 (PMID: 31427709) and 1 in 300,000 (PMID: 3487908). However, the prevalence of congenital stationary night blindness 1C specifically is unknown.

Penetrance: Penetrance is thought to be complete.

PMID: 18976725

Gene: EYS

HGNC: 21555

Disease: Retinitis pigmentosa 25

MONDO: MONDO:0011272

InheritancePattern: autosomal recessive

Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa caused by homozygous or compound heterozygous EYS variants is estimated to be 12% in the French population (PMID: 20333770), implying in an overall prevalence between 1 in 25,000 and 1 in 33,000.

Penetrance: The disease appears to be completely penetrant among published families.

PMID: 21127010

Gene: PDE6C

HGNC: 8787

Disease: cone dystrophy 4

MONDO: 0013129

InheritancePattern: recessive

Prevalence: cone dystrophy in general is estimated to have a prevalence of 1 in 40,000 (PMID: 30578485).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.

Selection A- Gene with same function implicated in disease

ExperimentName: Moye et al. 2018

GOterm: GO:0051179 (localization)

FunctionalEvidence: It was discovered that without ARL2BP, the photoreceptor OS does not develop normally or have correct DMT formation, axoneme extension, and disk alignment.

HGNC: HGNC:10295 (RPGR), HGNC:10263 (RP1), HGNC:6816 (MAK)

GeneEvidence: ARL2BP, RPGR, RP1 and MAK are all localized within the ciliary basal body and rootlet.

SharedGeneImplication: RPGR was classified as having a "definitive" relationship with RP 15 by the Retina GCEP. Refer to the curation for further details. RP1 was classified as having a "definitive" relationship with RP1 by the Retina GCEP. Refer to the curation for further details. MAK was classified as having a "definitive" relationship with MAK-related retinopathy by the Retina GCEP. Refer to the curation for further details.

Case#: Chang_2009_Family_CHRO9_Proband_II:3, female, age 26 years at time of report, family origin not described

CasePresentingHPOs: HP:0000613 (Photophobia), HP:0003593 (Infantile onset), HP:0001141 (Severely reduced visual acuity), HP:0011003 (High myopia), HP:0000551 (Color vision defect, described as complete lack of color discrimination), HP:0000603 (Central scotoma), HP:0030465 (Undetectable light-adapted electroretinogram), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram, described as extinguished), HP:0007401 (Macular atrophy)

CaseHPOFreeText: The proband and an affected family member were previously diagnosed with achromatopsia.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: Affected and unaffected family members were initially subjected to genotyping of the CNGA3, GNGB3, and GNAT2 loci, confirming absence of causal variants in these known achromatopsia-related genes.

CaseMethod1: Sanger sequencing of CNGA3, GNGB3, and GNAT2

CaseMethod2: Sanger sequencing of the 22 exons and flanking regions of PDE6C

CaseGenotypingMethod: CNGA3, GNGB3, and GNAT2 were previously screened / known not to harbor causal variants for achromatopsia. The family members were then subjected to Sanger sequencing of the 22 exons and flanking regions of PDE6C.

Variant: The proband harbors the NM_006204.4(PDE6C):c.481-12T>A and NM_006204.4(PDE6C):c.1483-2A>G variants in the compound heterozygous state.

ClinVar ID: 8770, 8771

gnomAD: The NM_006204.4(PDE6C):c.481-12T>A variant was not found in gnomAD v2.1.1. The NM_006204.4(PDE6C):c.1483-2A>G variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_006204.4(PDE6C):c.481-12T>A is an intronic variant that has been subjected to a mini-gene assay in COS7 cells and triggers a fully penetrant splicing defect (use of a cryptic splice site 10 nucleotides upstream, resulting in a frameshift encoding p.Asn161fsX169, Figure S5A). NM_006204.4(PDE6C):c.1483-2A>G is a canonical splice site variant that has been subjected to a mini-gene assay in COS7 cells and triggers a fully penetrant splicing defect (exon 12 skipping, resulting in an in-frame deletion encoding p.495_543del49, Figure S5B).

CaseAddInfo: The patient has an affected sister who shares the same compound heterozygous genotype, while the parents and one other sibling are each unaffected carriers.

CasePMIDs: N/A

PMID: 9843205

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age

PMID: 11095629

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 20

MONDO: 0013425

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.

Penetrance: Fully penetrant, with onset typically in childhood

PMID: 15331616

Gene: NYX

HGNC: 8082

Disease: Congenital stationary night blindness 1A

MONDO: 0010690

InheritancePattern: X-linked recessive

Prevalence: Congenital stationary night blindness has an estimated prevalence between 1 in 6,000 (PMID: 31427709) and 1 in 300,000 (PMID: 3487908). However, the prevalence of congenital stationary night blindness 1A specifically is unknown.

Penetrance: Penetrance is thought to be complete.

Case#: Bowne_2011_Family_TCD-G_Patient_53, male, unspecified age, family origin in Ireland

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient was initially diagnosed with retinitis pigmentosa prior to genotyping. Detailed phenotypes are not specified for individual patients.

CaseNotHPOs: HP:0003593 (Infantile onset), HP:0011463 (Childhood onset)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Candidate gene sequencing for variants in other known retinitis pigmentosa genes. SNP-based linkage analysis mapped the phenotype of autosomal dominant retinitis pigmentosa to an 8.8-Mb genomic region located at chr1 p31. It is not clear whether the patient was one of 3 affected individuals subjected to whole exome sequencing.

CaseMethod1: SNP-based linkage analysis and whole exome sequencing

CaseMethod2: Candidate gene sequencing

CaseGenotypingMethod: Sanger sequencing of 11 candidate genes among the 50 known genes from the mapped region, including RPE65 and PDE4B.

Variant: The patient harbors the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant in one allele of RPE65.

ClinVar: 750796

gnomAD: The NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was not found in gnomAD.

VariantEvidence: Exogenous expression of the variant reveals protein expression levels, cellular localization and retinoid isomerase activity comparable to the wild-type (PMID: 29659842). However, knock-in mouse models exhibit retinyl ester accumulation (PMID: 29659842), abnormally slow regeneration of 11-cis-retinal after light exposure, and ERG results indicative of delayed dark adaptation (PMID: 28041994). Mice with CRISPR-mediated knock-in of the variant also exhibit a splicing defect in RPE65 due to the introduction of a cryptic splice site, which likely triggers a frameshift, exclusion of exons 13 and 14 from the transcript, and premature truncation of the protein product (PMID: 30628748).

CaseAddInfo: N/A

CasePMIDs: PMID: 20861475, PMID: 16799052, PMID: 17982421, PMID: 17924349, PMID: 19520207, PMID: 17003455

FamilyLabel: Bowne_2011_Family_TCD-H

Family#PresentingHPOs: N/A

Family#PresentingHPOFreeText: Family members were provisionally diagnosed with choroideremia prior to genotyping.

FamilyNotHPOs: N/A

CountryOrigin: Ireland

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Candidate gene sequencing of the CHM locus to exclude the initial diagnosis of choroideremia

Family#Method1: Two-point linkage analysis of the RPE65 locus, as well as haplotype analysis using STR genotypes surrounding the variant of interest

Family#Method2: Candidate gene sequencing

Family#GenotypingMethod: Sanger sequencing of the RPE65 locus

Affected: 3

Unaffected: N/A

Segregations: 2 segregations were reported. The pedigree can be found in Figure 1c. Consanguinity of the family was not mentioned.

PublishedLOD: 5.3 (in combination with Family TCD-G, which shares a haplotype

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Bowne_2011_Family_TCD-H_Patient_01

Variant: Affected individuals harbor the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant in one allele of RPE65.

ClinVar: 750796

gnomAD: The NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was not found in gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: 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

Case#: F2-II:1, F, Age: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007994 (Peripheral visual field loss), HP:0032037 (Mildly reduced visual acuity), HP:0001328 (Specific learning disability/earning difficulties)

CaseHPOFreeText: FAF imaging in three patients demonstrated a ring of increased autofluorescence parafoveally in F2-II:1

OCT imaging also demonstrated loss of outer retina with partial preservation of the inner segment ellipsoid band in patient F2-II:1

Patients from families 2 and 3 initially developed nyctalopia, with a range of onset from 9 to 30 years before subsequent development of peripheral visual field loss. At last review (age range, 24–45 years), there was mild visual acuity loss with best-corrected visual acuity mean 0.34 logMAR (range, 0.30–0.48). All patients developed posterior subcapsular cataract. Patient F2-II:1 had learning difficulties but no other symptoms suggestive of syndromic disease. There were fundus abnormalities consistent with RP including attenuated vessels, macular and midperipheral RPE mottling/atrophy, and peripheral intraretinal pigment migration, most prominent in the proband of family 3 (Fig. 2I). Fundus autofluorescence imaging demonstrated a ring of increased autofluorescence parafoveally in F2-II:1

On OCT, there was outer retinal atrophy with variable preservation of photoreceptors most apparent in F2-II:1 with a centrally preserved inner segment ellipsoid band (Fig. 2D). Optical coherence tomography imaging demonstrated intraretinal cysts of the inner nuclear layer, which responded to topical carbonic anhydrase inhibitors (Figs. 2E, 2H, 2K). Electrophysiology demonstrated rod and cone system dysfunction (Table 1).

Two affected siblings from family 2 (GC15894) were homozygous for the missense variant c.323C>G:p.(Pro108Arg).

All patients had midperipheral reduced autofluorescence in keeping with regions of RPE atrophy and increased pigmentation.

All patients had midperipheral reduced autofluorescence in keeping with regions of RPE atrophy and increased pigmentation.

All patients developed posterior subcapsular cataract.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_021831.6:c.323C>G (p.Pro108Arg).

ClinVar: 1184585.

CAID: CA346170082.

gnomAD: Frequency: 2.800e-7. Link: https://gnomad.broadinstitute.org/variant/chr2-27053509-C-G?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: Affected sister F2-II:3 was noted to have the following:

Focal parafoveal increased autofluorescence in F2-II:3 (G), likely representing cystoid macular edema.

Very limited photoreceptor preservation for F2-II.3

Focally increased autofluorescence corresponding to macular edema in F2-II:3

CasePMIDs: N/A.

PMID: 18775863

Gene: PDE6A

HGNC: 8785

Disease: retinitis pigmentosa 43

MONDO: MONDO:0013437

InheritancePattern: autosomal recessive

Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a recessive mode of inheritance is estimated to be 65-85% (between 1 in 3,500 and 1 in 6,200). Retinitis pigmentosa 43 is considered to be make up 2-5% of these cases, with an overall prevalence estimated between 1 in 70,000 and 1 in 310,000.

Penetrance: Known disease-causing alleles appear to be completely penetrant.

Case#: Mancini_2015_Patient_III-6, female, age 52 at onset of visual symptoms, North-West Italian origin

CasePresentingHPOs: HP:0003596 (Middle age onset), HP:0002355 (Difficulty walking), HP:0001260 (Dysarthria), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001272 (Cerebellar atrophy), HP:0006855 (Cerebellar vermis atrophy), HP:0008278 (Cerebellar cortical atrophy), HP:0001251 (Ataxia), HP:0002317 (Unsteady gait), HP:0000639 (Nystagmus), HP:0001310 (Dysmetria), HP:0007350 (Hyperreflexia in upper limbs), HP:0002395 (Lower limb hyperreflexia), HP:0000736 (Short attention span), HP:0002075 (Dysdiadochokinesis), HP:0001123 (Visual field defect), HP:0030528 (Paracentral scotoma), HP:0000543 (Optic disc pallor), HP:0002346 (Head tremor)

CaseHPOFreeText: Presentation was at age 52, with visual loss (attributed to glaucoma) as the first phenotype manifested. Pale and excavated optic disc (bilateral) was consistent with severe glaucoma or previous lesion of optic nerve. Neurological symptoms were recognized at age 55 (gait instability, dysarthria, and mild cognitive deficit). Onset of slight attention deficit, nystagmus with vertical component, dysarthric slurred speech, mild head tremor, truncal ataxia, mild dysmetria and dysdiadochokinesia, ataxic gait / posture, brisk deep reflexes in all four limbs, marked cerebellar atrophy (particularly in the vermis), severe bilateral cortical atrophy (especially parietal and temporal), limited visual field (bilateral, with paracentral scotoma in the left eye only), and pale and excavated optic discs (bilateral) were found at age 58. Dysarthria worsened at age 61, when patient also exhibited an inability to walk unassisted, severe intentional tremor in the limbs, and severe cognitive impairment.

CaseNotHPOs: HP:0410280 (Pediatric onset), HP:0003474 (Somatic sensory dysfunction), HP:0002353 (EEG abnormality), HP:0040129 (Abnormal nerve conduction velocity),

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing was limited to molecular tests ruling out Friedreich Ataxia and Spinocerebellar Ataxia types 1 and 2.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Whole exome sequencing of the proband and the affected sibling. Homozygosity was assumed due to the consanguinity of the family, contributing to the decision to focus on the variant in CLN5. This variant was confirmed by Sanger sequencing of PCR products from exon 4 of the CLN5 gene in both affected family members and an additional unaffected sibling. Parents were not subjected to genotyping.

Variant: The proband is homozygous for the NM_006493.4(CLN5):c.788G>A (p.Ser263Asn) variant.

ClinVar: 183049 (homozygous)

gnomAD: The maximum allele frequency for the NM_006493.4(CLN5):c.788G>A (p.Ser263Asn) variant is 0.000008805 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/13-77574815-G-A

VariantEvidence: The variant encodes a missense substitution that results in aberrant retention in the ER compartment rather than proper localization to lysosomal vesicles (Figs. 1E-1J).

CaseAddInfo: Family is consanguineous (parents were first cousins).

CasePMIDs: N/A

PMID: 27302685

review article

Case#: Gong_2001_Proband_2, no reported gender, age or national origin

CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)

CaseHPOFreeText: The proband has been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1), but it is not clear whether this proband was a member of one of these kindreds.

CaseMethod1: Linkage analysis with additional markers around a strong candidate marker

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

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

Variant: The patient harbors the NM_002335.4(LRP5):c.1282C>T (p.Arg428Ter) variant in the homozygous state.

ClinVar: 6269

gnomAD: The NM_002335.4(LRP5):c.1282C>T (p.Arg428Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.1282C>T (p.Arg428Ter) is a nonsense variant in exon 6 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~74% of the protein product.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

Case#: Aldahmesh_2010_Family_Proband_II-1, male, onset in early childhood, age 12 years at time of report, family ancestry reported as Dutch

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity), HP:0000613 (Photophobia), HP:0000551 (Color vision defect)

CaseHPOFreeText: The proband and his sibling have a diagnosis of cone-rod dysfunction, including color vision described as severely abnormal and electroretinogram responses that showed absent cone a-wave but normal-to-subnormal rod function.

CaseNotHPOs: HP:0000662 (Nyctalopia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to homozygosity mapping of the sibling and his affected sister that identified a shared region of homozygosity on chromosome 13.

CaseMethod1: Homozygosity mapping

CaseMethod2: Sanger sequencing of CABP4

CaseGenotypingMethod: Genotyping began with homozygosity mapping of the sibling and his affected sister that identified a shared region of homozygosity on chromosome 13, followed by Sanger sequencing of PCR products from the CABP4 gene.

Variant: The individual harbors the NM_145200.5(CABP4):c.646C>T (p.Arg216Ter) variant in the homozygous state.

ClinVar ID: 190959

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.0001418 in the European (non-Finnish) population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/chr11-67457677-C-T?dataset=gnomad_r4

VariantEvidence: NM_145200.5(CABP4):c.646C>T (p.Arg216Ter) is a nonsense variant within exon 4 of 6 that is predicted to trigger nonsense-mediated decay.

CaseAddInfo: The proband's family includes a similarly affected sister harboring the variant in the homozygous state, and unaffected parents who each carry the variant in the heterozygous state. Consanguinity has not been commented upon.

CasePMIDs: N/A

PMID: 32203983

GeneName: GNAT2

HGNC: 4394

Disease: achromatopsia 4

MonDO ID: MONDO_0013465

Inheritance: autosomal recessive

FamilyLabel: Corton_2010_Family_RP-72

Family#PresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000540 (Hypermetropia), HP:0007663 (Reduced visual acuity), HP:0001133 (Constriction of peripheral visual field), HP:0000550 (Undetectable electroretinogram), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007401 (Macular atrophy), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor)

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with retinitis pigmentosa segregating with an autosomal recessive mode of inheritance.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Spain / Galicia

Ethnicity: Spanish

Race: Not specifically described

Family#PreviousTesting: N/A

Family#Method1: Haplotype analysis

Family#Method2: Sanger sequencing of 3 candidate genes; PDE6A, PDE6B, and RHO

Family#GenotypingMethod: Haplotype analysis was performed in affected and unaffected family members to identify candidate regions of homozygosity in all affected individuals. Sanger sequencing was then performed on PCR products of exons and flanking regions from the PDE6A, PDE6B, and RHO loci.

Affected: 4

Unaffected: 5 fully genotyped

Segregations: 4 segregations are shown by the pedigree in Figure 1a.

PublishedLOD: N/A

eLOD: 2.43

AddSegregationInfo: N/A

ProbandLabel: Corton_2010_Family_RP-72_patient_IV:2

Variant: The affected family members harbor the NM_000440.3(PDE6A):c.2053G>A (p.Val685Met) variant in the homozygous state.

ClinVar: 29874

gnomAD: In gnomAD v2.1.1, NM_000440.3(PDE6A):c.2053G>A (p.Val685Met) has a frequency of 0.00008531 (11/128938) in the European non-Finnish population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/5-149263074-C-T

VariantEvidence: A mutation equivalent to this variant in the homozygous nmf28/nmf28 mouse model caused grainy abnormalities in fundus pigmentation associated with loss of most photoreceptor cells shortly after birth, as well as loss of cGMP-PDE6 activity resulting in increased intracellular cGMP levels (PMID: 18849587).

FamilyAddInfo: The family includes multiple consanguineous unions, including the proband's parents, and three affected paternal aunts.

FamilyPMIDs: N/A

PMID: 25085631

Gene: IMPG2

HGNC: 18362

Disease: retinitis pigmentosa 56

MONDO: 0013314

InheritancePattern: semi-dominant

Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.

ExperimentName: Rescue in patient-derived IPSC cells harboring IFT140 variants

RescueProband: Forbes_2018_Proband_1 has been diagnosed with retinitis pigmentosa (age 1), end-stage kidney disease (age 6), and Mainzer-Saldino syndrome (at the time of this study). The proband and her non-consanguineous parents were genotyped by Trio whole exome sequencing, identifying compound heterozygous (paternal and maternal) IFT140 variants in the proband.

GeneAlteration: The proband harbors the NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) and NM_014714.4(IFT140):c.2176C>G (p.Pro726Ala) variants in trans. The former variant has been shown to mislocalize when exogenously expressed as a cDNA, and is predicted to disrupt a donor splice site (SpliceAI change score of 0.61).

RescueVariant: The variant rescued by CRISPR/Cas9-based gene editing was NM_014714.4(IFT140):c.634G>A (p.Gly212Arg), (ClinVar ID: 31683). This variant was corrected at the same time as a synonymous 3 bp change was introduced to facilitate the detection of the editing event.

RescuedPhenotype: Patient IPSC-derived organoids exhibit Short / clubbed cilia with swollen sips (Figure 3A-3C), Approximately 50% expression of IFT140 at both the mRNA and protein levels (Figures 2D, 2E), and Disturbed apicobasal polarity compromising the ability of iPSC cells to establish polarized spheroids (Figures 5C, 5D).

RescueMethod: CRISPR/Cas9-based gene editing was used to correct one of the proband's two variants (NM_014714.4(IFT140):c.634G>A (p.Gly212Arg), (ClinVar ID: 31683)). A synonymous 3 bp change was simultaneously introduced to facilitate the detection of the editing event.

RescueEvidence: Gene-corrected cells had longer ciliary length with reduced clubbing (Figure 3), approximately twice the expression of IFT140 at the mRNA and protein levels (Figures 2D, 2E), and a higher percentage of polarized spheroids established in organoid culture (indicating recovery of apicobasal polarity).

PMID: 19853238

Gene: BEST1

PMID: 24069149

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.

ExperimentName: Morpholino-based knockdown of zbbs1 disrupts ciliary beating pattern.

NonHumanModel: Danio rerio

GeneAlteration: The model animals have been subjected to morpholino-based knockdown of zbbs1, the zebrafish ortholog of human BBS1.

ModelPhenotype: HP:0012262 (Abnormal ciliary motility), HP:0000107 (Renal cyst)

HumanPhenotype: HP:0000639 (Nystagmus), HP:0000510 (Rod-cone dystrophy), HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0000107 (Renal cyst), HP:0001513 (Obesity), HP:0010442 (Polydactyly), HP:0002463 (Language impairment), HP:0000026 (Male hypogonadism)

ModelEvidence: Morpholino-based knockdown of the zbbs1 gene causes hydrocephalus (Figure 3B), formation of pronephritic cysts (Figure 3G), embyronic body axis abnormalities (Figure 4B), heart looping defects (Figure 5B), longer cilia (Figure 7F), and normal ciliary ultrastructure (Figure 7I), and aberrant ciliary motility in the pronephritic tubule and nasal pit (Supplementary Movies).

ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied the effects of silencing the gene product.

ExperimentName: CRISPR/Cas9-based disruption of mouse Impg2

NonHumanModel: Mus musculus

GeneAlteration: Model animals were subjected to CRISPR/Cas9-based deletion of 166bp from exon 2 of Impg2, and analyzed in the homozygous state. Absence of Impg2 signal was confirmed by RT-PCR. Mice were studied at ages 3, 6, and 13 months.

ModelPhenotype: HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0000580 (Pigmentary retinopathy), HP:0030609 (Photoreceptor layer loss on macular OCT)

HumanPhenotype: HP:0000529 (Progressive visual loss), HP:0000662 (Nyctalopia), HP:0000551 (Color vision defect), HP:0008002 (Abnormality of macular pigmentation), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0000533 (Chorioretinal atrophy), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007994 (Peripheral visual field loss), HP:0000603 (Central scotoma)

ModelEvidence: Abnormalities of the homozygous Impg2 deletion mice included reduction in the amplitudes of ERG responses from both rods and cones at age 6 months (Figure 2). Pigmentary retinopathy was also observed (Figure 2C), as well as progressive photoreceptor layer loss (Figure 3). Cone markers such as PNA and M-opsin were mislocalized (Figure 4), indicating cone cell disorganization. Enhanced apoptosis was also observed in the photoreceptor cell segments (Figure 5), consistent with the decreased outer nuclei layer thickness.

ModelVariant: The model does not introduce a variant previously observed in human patients, but rather disrupts the expression of the Impg2 ortholog.

PMID: 19536307

Gene: TIMP3

HGNC: 11822

Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy

MONDO: 0007640

InheritancePattern: Autosomal Dominant

Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)

Penetrance: Fully penetrant, onset between the third and sixth decades of life

PMID: 9855162

Gene: RPGR

HGNC: 10295

Disease: RPGR-related retinopathy

MONDO: MONDO:0100437

InheritancePattern: X-linked

Prevalence: The prevalence of RPGR-related retinopathy is calculated to be approximately 1 in 214,000, based on the known incidence of retinitis pigmentosa at 1 in 3,000, the proportion of retinitis pigmentposa that is X-linked at 20%, and the proportion of X-linked retinitis pigmentosa that is RPGR-associated at 70% (PMID: 34985506).

Penetrance: Penetrance is nearly 100% in hemizygous males but is incomplete and dependent upon the variant in heterozygous female carriers.

PMID: 23189188

ExperimentName: GPR143 silencing in melanoma cells

NonPatientCell: CL:1000458 (melanocyte of skin, specifically the highly pigmented MNT-1 human melanoma cell line)

GeneFunction: GO:1903232 (melanosome assembly)

GeneAlteration: GPR143 silencing was accomplished by transient transfection of MNT-1 cells with specific siRNA, alongside a non-targeting siRNA control.

FunctionalEvidence: siRNA-treated cells exhibited 50% reduction in mature melanosomes and melanin-containing cells by immunofluorescence (Figures 2E, 2F, 2G). This was confirmed by electron microscopy (Figures 2H, 2I, 2J, 2K). GPR143 silencing also resulted in a combination of normal sized melanosomes and enlarged macromelanosome precursors (Figures 2I, S2A). These cellular defects are an approximate match to the giant melanosomes in the melanocytes of the human patients as well as the hypopigmentation of the fundus.

FAVariants: GPR143 disruption was siRNA-based, and patient-associated variants were not studied.

PMID: 30319355

Gene: GUCY2D

HGNC: 4689

Disease: Cone-rod dystrophy 6

MONDO: 0011143

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of cone-rod dystrophy is between 1 in 30,000 and 1 in 40,000 (PMID: 17270046), while the proportion of cone-rod dystrophy caused by GUCY2D variants is between 19% and 23% (PMID: 22183351, PMID: 25515582). Thus, the prevalence of cone-rod dystrophy 6 is between 1 in 130,000 and 1 in 215,000.

Penetrance: Penetrance is age-dependent, with onset between the 1st and 6th decades of life.