PMID: 19074807

Gene: CABP4

HGNC: 1386

Disease: cone-rod synaptic disorder, congenital nonprogressive

MONDO: 0012490

InheritancePattern: autosomal recessive

Prevalence: The prevalence of the Åland eye disease or incomplete congenital stationary night blindness phenotype was estimated at 1 in 22,000 based on a Danish male cohort, with CABP4 variants specifically responsible for 1 out of 35 cases (PMID: 28002560).

Penetrance: Penetrance appears to be 100% among the reported individuals harboring biallelic disease-causing CABP4 variants.

Case#: Holmberg_Patient_8, female, age 3 at onset and age 19 at time of study, Swedish 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: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), HP:0002059 (Cerebral atrophy), HP:0001272 (Cerebellar atrophy)

CaseHPOFreeText: Age of onset was 3, while mental decline was found at age 7. Visual deterioration and Seizures developed at age 8. Ataxia and Giant flash visual evoked potentials had onset at age 9. 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. Cerebral atrophy was slight at age 8.9 years, but had progressed to severe cerebral and cerebellar atrophy by age 17.

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 a compound heterozygote harboring the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) and NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variants.

ClinVar: 2565, 56543

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 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.78G>A (p.Trp26Ter) is a recurring nonsense variant that is predicted to trigger nonsense-mediated decay of CLN5. NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) is 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

GroupName: Holmberg_Group_1

GroupPresentingHPOs: 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: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)

GroupHPOFreeText: 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.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

NumberMales: 4

NumberFemales: 4

CountryOrigin: Finland / Sweden / Netherlands

Ethnicity: Finnish / Swedish / Dutch

Race: Not mentioned

AgeRange: 2-4 years old at onset, 7-19 years old at time of study

TotalNumber: 8

FamilyInfo: 0

NoFamily: 8

VariantCount: 8

NonVariant: 0

OtherVariant: 0

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

GroupMethod1: N/A

GroupMethod2: N/A

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

GroupAddInfo: N/A

Case#: Holmberg_Patient_4, female, age 3 at onset and age 13 at time of study, Finnish origin

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

CaseHPOFreeText: Age of onset was 3, while visual deterioration was found at age 6. Mental decline was found at age 7, while abolished ERG and Giant flash visual evoked potentials were present at age 8. Ataxia, Seizures, and Loss of independent walking occurred at age 11. 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#: Morimura_1998_Family_9404_Patient_II-3, 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 homozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.2T>C (p.Met1Thr) variant.

ClinVar: 98861 (homozygous)

gnomAD: The NM_000329.3(RPE65):c.2T>C (p.Met1Thr) variant was not found within gnomAD.

VariantEvidence: NM_000329.3(RPE65):c.2T>C (p.Met1Thr) is a missense variant that disrupts the start codon and is therefore predicted to have gene impact.

CaseAddInfo: Other family members were not genotyped, and potential consanguinity between the parents was not reported.

CasePMIDs: N/A

Case#: Morimura_1998_Family_0748_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.643+2T>A variant.

ClinVar: 940479 (homozygous)

gnomAD: The NM_000329.3(RPE65):c.643+2T>A variant is not found within gnomAD.

VariantEvidence: NM_000329.3(RPE65):c.643+2T>A is an intron 6 variant strongly predicted to disrupt a canonical splice donor site (with a delta score of 0.98).

CaseAddInfo: While the variant is known to be homozygous, the proband's parents have not been genotyped. The potential consanguinity of the parents was not mentioned.

CasePMIDs: N/A

ExperimentName: GPR143 interacts with TYR by co-IP and FRET

InteractingGene: TYR, which is implicated in oculocutaneous albinism types 1A and 1B

InteractionType: Physical

InteractionMethod: Co-immunoprecipitation and FRET were both performed with positive results.

InteractionEvidence: Co-IP of the exogenously expressed GPR143 fusion protein or endogenous TYR found that IP of one protein pulls down the other as well (Figure 2). This was confirmed by fluorescent resonance energy transfer experiments (Figures 4 and 5). Use of a mislocalizing GPR143 mutant control showed that TYR localization appears to be GPR143-dependent (Figures 3 and 4).

PMID: 10601738

Gene: IMPG1

HGNC: 6055

Disease: vitelliform macular dystrophy 4

MONDO: 0014508

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.

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

ExperimentName: IMPG1 protein ("IPM150") expression within eye tissues is localized to cone and rod photoreceptor cells in the outer nuclear layer.

TissueExpression: UBERON:0001789 (outer nuclear layer of retina)

ExpressionEvidence: In situ hybridization within eye tissues detects IMPG1 expression in the cone and rod photoreceptor cells, specifically in the outer nuclear layer (Figure 8).

Case#: Meindl_1996_Family_RP49_Proband, male, age not specified, family origin either German or British

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy)

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa. Disease onset was reported as early.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The family members previously underwent linkage analysis to map the underlying genetic cause to the region on chromosome Xp21.1 between the CYBB and OTC genes.

CaseMethod1: Hybridization analysis of amplified cDNA fragments from the RPGR locus to look for deletions, and SSCP analysis to look for point mutations

CaseMethod2: Sanger sequencing of the RPGR locus

CaseGenotypingMethod: The family members previously underwent linkage analysis to map the underlying genetic cause to the region on chromosome Xp21.1 between the CYBB and OTC genes. Amplified cDNA fragments from the RPGR locus were then screened by hybridization analysis to look for deletions and SSCP analysis to look for point mutations. The presence of the variant was confirmed by Sanger sequencing of the RPGR locus.

Variant: The affected family members harbor the NM_001034853.2(RPGR):c.644G>T (p.Gly215Val) variant in the hemizygous state.

ClinVar: 98794

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

VariantEvidence: NM_001034853.2(RPGR):c.644G>T (p.Gly215Val) is a missense variant in exon 7 of 15 and has been shown to disrupt the ability of the protein product to interact with PDE6D, INPP5E, and RPGRIP1L (PMID: 30622176, Figure 4).

CaseAddInfo: The proband is a member of Family RP49.

CasePMIDs: N/A

FamilyLabel: Meindl_1996_Family_F47

Family#PresentingHPOs: N/A

FamilyPresentingHPOFreeText: Affected family members have been diagnosed with retinitis pigmentosa, with an X-linked pattern of inheritance.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Not specified

Ethnicity: Not specified

Race: Not specifically mentioned

Family#PreviousTesting: The family members previously underwent linkage analysis to map the underlying genetic cause to the region on chromosome Xp21.1 between the CYBB and OTC genes.

Family#Method1: Hybridization analysis of amplified cDNA fragments from the RPGR locus to look for deletions, and SSCP analysis to look for point mutations

Family#Method2: Sanger sequencing of the RPGR locus

Family#GenotypingMethod: The family members previously underwent linkage analysis to map the underlying genetic cause to the region on chromosome Xp21.1 between the CYBB and OTC genes. Amplified cDNA fragments from the RPGR locus were then screened by hybridization analysis to look for deletions and SSCP analysis to look for point mutations. The presence of the variant was confirmed by Sanger sequencing of the RPGR locus.

Affected: 3

Unaffected: N/A

Segregations: 8 segregations are shown by the pedigree in Figure 6.

PublishedLOD: N/A

eLOD: 2.4

AddSegregationInfo: N/A

ProbandLabel: Meindl_1996_Family_F47_Proband

Variant: The affected family members harbor the NM_001034853.2(RPGR):c.294C>A (p.His98Gln) variant in the hemizygous state.

ClinVar: 98775

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

VariantEvidence: NM_001034853.2(RPGR):c.294C>A (p.His98Gln) is a missense variant and does not have associated evidence of impact on RPGR function.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

PMID: 26072023

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.

PMID: 35272502

Gene: OPN1LW

HGNC: 9936

Disease: protan color blindness

MONDO: 0010565

InheritancePattern: X-linked

Prevalence: The overall prevalence of protan color blindness is approximately 1% in males, which is higher than that of blue cone monochromacy (~1 in 100,000, PMID: 35759666).

Penetrance: Known disease-causing alleles appear to be almost completely penetrant in males (PMID: 21167193).

PMID: 25475713

Gene: KCNJ13

HGNC: 6259

Disease: Leber congenital amaurosis 16

MONDO: 0013613

InheritancePattern: autosomal recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns (PMID: 10951519), while the proportion of Leber congenital amaurosis caused by KCNJ13 variants is unknown.

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

Case#: Khan_2015_Proband, female, age 12 years, family national origin described as Saudi

CasePresentingHPOs: Congenital nystagmus HP:0006934, Juvenile cataract HP:0001118, Reduced visual acuity HP:0007663, Posterior cortical cataract HP:0010924, Abnormal optic disc morphology (fibrosis over the optic disc) HP:0012795, Pigmentary retinopathy HP:0000580, Undetectable light-adapted electroretinogram HP:0030465, Abnormal dark-adapted electroretinogram (decreased amplitude) HP:0030469

CaseHPOFreeText: The proband's overall phenotype was summarized as "juvenile cataract in the setting of a congenital vitreo-retinal dystrophy notable for fibrosis over the disc and clumped pigmentation in the posterior pole". The authors comment that the phenotype should be described as; "early-onset vitreo-retinal degeneration (with early-onset cataract)" rather than as LCA, due to the presence of vitreous degenerative changes as well as the ERG being recordable in patients in the second decade of life and beyond.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was initially genotyped by next-generation sequencing focused on a panel of 27 LCA genes and 60 recessive retinitis pigmentosa genes.

CaseMethod1: next-generation sequencing focused on a panel of 27 LCA genes and 60 recessive retinitis pigmentosa genes

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

CaseGenotypingMethod: The proband was initially genotyped by next-generation sequencing focused on a panel of 27 LCA genes and 60 recessive retinitis pigmentosa genes. Sanger sequencing of the proband and family members was then performed to confirm the presence of the variant and to test segregation.

Variant: The individual is homozygous for the NM_002242.4(KCNJ13):c.359T>C (p.Ile120Thr) variant.

ClinVar: 191155

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.00001562 (1 allele / 64034 total alleles) in the European (Finnish) population https://gnomad.broadinstitute.org/variant/2-232771004-A-G?dataset=gnomad_r4

VariantEvidence: NM_002242.4(KCNJ13):c.359T>C (p.Ile120Thr) is a missense variant that has not been studied at the functional level.

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

CasePMIDs: N/A

PMID: 15452577

Gene: CABP4

HGNC: 1386

Disease: cone-rod synaptic disorder, congenital nonprogressive

MONDO: 0012490

InheritancePattern: autosomal recessive

Prevalence: The prevalence of the Åland eye disease or incomplete congenital stationary night blindness phenotype was estimated at 1 in 22,000 based on a Danish male cohort, with CABP4 variants specifically responsible for 1 out of 35 cases (PMID: 28002560).

Penetrance: Penetrance appears to be 100% among the reported individuals harboring biallelic disease-causing CABP4 variants.

Case#: Arno_2015_Family_GC19774_Patient_3, male, first seen at age 2 years, family origin not reported

CasePresentingHPOs: HP:0025313 (Exophoria), HP:0000545 (Myopia), HP:6001439 (Tigroid fundus), HP:0012795 (Abnormal optic disc morphology, specifically myopic discs), HP:0007663 (Reduced visual acuity), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0030844 (Undetectable pattern electroretinogram)

CaseHPOFreeText: BCVA was 0.350 / 0.325 logMAR (Snellen 20/50 or 20/40). OCT showed loss of inner segment-ellipsoid over peripheral macular areas. Initial ERG showed rod more affected than cone. Later ERG showed more severe cone deterioration. Overall phenotype was summarized as "high myopia and retinal dystrophy in childhood with no significant fundus changes".

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was by whole exome sequencing.

CaseMethod1: WES

CaseMethod2: Sanger sequencing of RBP3

CaseGenotypingMethod: Genotyping was performed by whole exome sequencing, followed by Sanger sequencing of RBP3.

Variant: The individual harbors the NM_002900.3(RBP3):c.1530T>A (p.Tyr510Ter) variant in the homozygous state.

CAID: CA376670175

gnomAD: The variant was not found in gnomAD version 4.1.1.

VariantEvidence: NM_002900.3(RBP3):c.1530T>A (p.Tyr510Ter) is a nonsense variant within exon 1 of 4 that is predicted to trigger nonsense-mediated decay.

CaseAddInfo: The proband comes from a consanguineous family with a similarly affected younger sibling sharing the same homozygous genotype.

CasePMIDs: N/A

Case#: Arno_2015_Family_GC17452_Patient_2, female, first seen at age 4 years, family origin not reported

CasePresentingHPOs: HP:0011003 (High myopia), HP:0000662 (Nyctalopia), HP:0030534 (Abnormal best corrected visual acuity test), HP:6001439 (Tigroid fundus), HP:0030602 (Abnormal fundus autofluorescence imaging, specifically patchy increased FAF in the vascular arcades), HP:0030603 (Abnormal optical coherence tomography, specifically showing loss of inner segment-ellipsoid over peripheral macular areas), HP:0008275 (Abnormal light-adapted electroretinogram, specifically showing delay and amplitude reduction of cone responses)

CaseHPOFreeText: BCVA was 0.550 / 0.575 logMAR (Snellen 20/80). FAF showed increased signal in vascular arcades, OCT showed loss of inner segment-ellipsoid over peripheral macular areas, ERG showed delay and amplitude reduction of cone responses. Overall phenotype was summarized as "high myopia and retinal dystrophy in childhood with no significant fundus changes".

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was by whole exome sequencing.

CaseMethod1: WES

CaseMethod2: Sanger sequencing of RBP3

CaseGenotypingMethod: Genotyping was performed by whole exome sequencing, followed by Sanger sequencing of RBP3.

Variant: The individual harbors the NM_002900.3(RBP3):c.3454G>T (p.Glu1152Ter) variant in the homozygous state.

CAID: CA376677245

gnomAD: The variant was not found in gnomAD version 4.1.1.

VariantEvidence: NM_002900.3(RBP3):c.3454G>T (p.Glu1152Ter) is a nonsense variant within exon 4 of 4 that is predicted not to trigger nonsense-mediated decay but rather to truncate the C-terminal 8% of the protein product.

CaseAddInfo: The proband comes from a consanguineous family with a similarly affected older sibling sharing the same homozygous genotype.

CasePMIDs: N/A

FamilyLabel: Perrault_2000_Family_9

Family#PresentingHPOs: N/A

Family#PresentingHPOFreeText: Affected family members are described as having Leber congenital amaurosis.

FamilyNotHPOs: N/A

CountryOrigin: Algeria

Ethnicity: Arab

Race: Not described

Family#PreviousTesting: Linkage mapping of the disease locus to chromosome 17p13.1 (PMID: 7581387, PMID: 8641699)

Family#Method1: Sanger sequencing of PCR products from each of the 20 exons

Family#Method2: N/A

Family#GenotypingMethod: Family members were initially subjected to homozygosity mapping, establishing linkage to chromosome 17p13.1 and particularly between the D17S1353 and D17S1854 markers (PMID: 7581387, PMID: 8641699). Subsequent genotyping was performed by Sanger sequencing of PCR products from the GUCY2D locus.

Affected: 4

Unaffected: 2

Segregations: 3 segregations were reported, with none inconsistent with the proposed mechanism of inheritance (Figure 3a). The family is reportedly consanguineous.

PublishedLOD: N/A

eLOD: 2.06

AddSegregationInfo: N/A

ProbandLabel: Perrault_2000_Family_9_Proband

Variant: Affected individuals are homozygous for the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant.

ClinVar: 9350

gnomAD: The variant exhibits a maximum allele frequency of 0.000008790 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7912849-T-C?dataset=gnomad_r2_1

FamilyAddInfo: N/A

FamilyPMIDs: PMID: 7581387, PMID: 8641699

Case#: Perrault_2000_Family_11_Proband, FEmale, age unknown, family origin in Algeria with Arab ancestry

CasePresentingHPOs: N/A

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Linkage mapping of the disease locus to chromosome 17p13.1 (PMID: 7581387, PMID: 8641699)

CaseMethod1: Sanger sequencing of PCR products from each of the 20 exons

CaseMethod2: N/A

CaseGenotypingMethod: The individual was included in multi-family homozygosity mapping, establishing linkage to chromosome 17p13.1 and particularly between the D17S1353 and D17S1854 markers (PMID: 7581387, PMID: 8641699). Subsequent genotyping was performed by Sanger sequencing of PCR products from the GUCY2D locus.

Variant: The individual is homozygous for the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant.

ClinVar: 9350

gnomAD: The variant exhibits a maximum allele frequency of 0.000008790 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7912849-T-C?dataset=gnomad_r2_1

VariantEvidence: The evidence supporting the pathogenicity of the variant is limited to computational prediction alone.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 7581387, PMID: 8641699

Case#: Perrault_2000_Family_12_Proband, Female, age unknown, family origin in Tunisia with Arab ancestry

CasePresentingHPOs: N/A

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Linkage mapping of the disease locus to chromosome 17p13.1 (PMID: 7581387, PMID: 8641699)

CaseMethod1: Sanger sequencing of PCR products from each of the 20 exons

CaseMethod2: Single strand conformational polymorphism analysis

CaseGenotypingMethod: The individual was included in multi-family homozygosity mapping, establishing linkage to chromosome 17p13.1 and particularly between the D17S1353 and D17S1854 markers (PMID: 7581387, PMID: 8641699). Subsequent genotyping was performed by SSCP and by Sanger sequencing of PCR products from all 20 exons of the GUCY2D locus.

Variant: The individual is homozygous for the NM_000180.4(GUCY2D):c.622del (p.Arg208GlyfsTer8) variant.

ClinVar: 98607

gnomAD: The variant is absent from gnomAD version 2.1.1.

VariantEvidence: The NM_000180.4(GUCY2D):c.622del (p.Arg208GlyfsTer8) variant is predicted to trigger nonsense mediated decay or to disrupt ~81% of the protein product by frameshift.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 7581387, PMID: 8641699

PMID: 12567324

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.

Case#: Badano_2003_Family_KK26_Proband_05, gender, age, and origin not reported.

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient has been diagnosed with Bardet-Biedl syndrome. Specific phenotypes have not been described in detail.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of linkage mapping using a 10-cM linkage map set to identify regions of homozygosity unique to the affected family member only.

CaseMethod1: Homozygosity analysis

CaseMethod2: Sanger sequencing of the BBS7 locus

CaseGenotypingMethod: Genotyping first identify regions of homozygosity unique to the affected family member, then performed Sanger sequencing of the BBS7 locus.

Variant: The patient harbors the NM_176824.3(BBS7):c.709_712del (p.Lys237fs) variant in the homozygous state.

ClinVar ID: 3017

gnomAD: The NM_176824.3(BBS7):c.709_712del (p.Lys237fs) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_176824.3(BBS7):c.709_712del (p.Lys237fs) 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 67% of the protein product.

CaseAddInfo: The proband is a member of family KK26, which is known to be consanguineous. The proband has two unaffected carrier parents, 5 unaffected carrier siblings, and 1 unaffected non-carrier sibling.

CasePMIDs: N/A

Case#: Olivier_2021_Family_B_Proband_II:2, female, age not specified, ethnic origin reported as French

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0030643 (Vitelliform-like retinal lesions), HP:0011506 (Choroidal neovascularization),

CaseHPOFreeText: The patient has a diagnosis of vitelliform macular dystrophy, and reportedly has a hyperreflective deposit in one eye.

CaseNotHPOs: HP:0000512 (Abnormal electroretinogram), HP:0030454 (Abnormal electrooculogram)

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of IMPG1 using gene panel testing and Sanger sequencing-based confirmation

CaseMethod2: Haplotype analysis using the microsatellite markers D6S1622, D6S456, D6S1589 and D6S251, spanning a 7.2-Mb region surrounding IMPG1.

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

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

ClinVar ID: 1240018

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

VariantEvidence: NM_001563.4:c.1824+1G>A is an intronic variant disrupting a canonical splice site in intron 13 (of the 17-exon gene), with unknown consequences for IMPG1 splicing.

CaseAddInfo: This family has helped establish the incomplete penetrance of the variant, as the patient's two sisters were asymptomatic carriers with normal fundus findings at ages 45 and 50 years respectively. The patient's 70-year-old mother was also a carrier and exhibited low vision.

CasePMIDs: N/A

ExperimentName: Morpholino-based disruption of Impg1 in medaka fish

NonHumanModel: Oryzias latipes

GeneAlteration: Model animals were subjected to targeted disruption of Impg1 by morpholino-based silencing.

ModelPhenotype: HP:0030610 (Photoreceptor outer segment loss on macular OCT).

HumanPhenotype: HP:0007754 (Macular dystrophy), HP:0007769 (Peripheral retinal degeneration), HP:0032037 (Mildly reduced visual acuity, progressive), HP:0008179 (Decreased Arden ratio of electrooculogram)

ModelEvidence: Morpholino-injected animals exhibit decreased photoreceptor outer segment length, especially for cones (Figures 4I, 4J).

ModelVariant: The model does not introduce a variant previously observed in human patients, but rather disrupts the expression of the Impg1 ortholog using a morpholino.

Case#: Xin_Patient_2, sex not mentioned, age 5-6 at onset, U.S. nationality, admixed European non-Finnish 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: Seizure was the phenotype at presentation (age 5). Motor difficulty, visual loss, and cognitive regression had onset at age 6.

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 harbors the NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) and NM_006493.4(CLN5):c.760_947del (p.Thr254CysfsTer10) variants.

ClinVar: 56544

CAID: CA2017997733

gnomAD: Maximum allele frequency for NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) is 0.00003517 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77570221-G-A The NM_006493.4(CLN5):c.760_947del (p.Thr254CysfsTer10) variant is not found in gnomAD.

VariantEvidence: NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) is a nonsense variant that results in truncation of approximately 51% of the protein product. The NM_006493.4(CLN5):c.760_947del (p.Thr254CysfsTer10) variant triggers a frameshift that affects the final 106 amino acids (approximately 29%) of the protein product. While neither variant is predicted to trigger NMD, the C-terminal region disrupted in both cases has been shown to be glycosylated and is important for proper localization of the protein (PMID:19309691).

CaseAddInfo: Parents do not appear to have been genotyped, so it is not clear whether the two variants are confirmed to be in trans.

CasePMIDs: N/A

Case#: Xin_Patient_7, sex not mentioned, age 4 at onset, U.S. nationality, Chinese ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset)

CaseHPOFreeText: Visual loss was the phenotype at presentation (age 4). Motor difficulty (age 5), Cognitive regression (age 5), and Seizure (age 6) had later onset.

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 harbors the NM_006493.4(CLN5):c.473G>C (p.Trp158Ser) and NM_006493.4(CLN5):c.924_925del (p.Leu309AlafsTer4) variants.

ClinVar: 56542, 56526

gnomAD: Both the NM_006493.4(CLN5):c.473G>C (p.Trp158Ser) and NM_006493.4(CLN5):c.924_925del (p.Leu309AlafsTer4) variants are absent from gnomAD.

VariantEvidence: NM_006493.4(CLN5):c.924_925del (p.Leu309AlafsTer4) is a frameshift variant that disrupts approximately 14% of the protein product. The NM_006493.4(CLN5):c.473G>C (p.Trp158Ser) missense variant affects a conserved residue but does not have other evidence of gene impact.

CaseAddInfo: Parents do not appear to have been genotyped, so it is not clear whether the two variants are confirmed to be in trans.

CasePMIDs: N/A

GroupName: Xin_2010_Group_1

GroupPresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration)

GroupNotHPOs: N/A

NumberMales: Not mentioned

NumberFemales: Not mentioned

CountryOrigin: United States (9 patients) or Sweden (1 patient)

Ethnicity: The 10 patients had various ethnicities; Admixture of French Canadian / Irish / U.K. / Dutch, Admixture of European non-Finnish (3 individuals), Hispanic, Chinese, Indian, Egyptian, Pakistani, Swedish

Race: Not mentioned

AgeRange: Between 4 and 17 years of age at onset

TotalNumber: 10

FamilyInfo: 0

NoFamily: 10

VariantCount: 10

NonVariant: 0

OtherVariant: 0

GroupPreviousTesting: 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.

GroupMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

GroupMethod2: as mentioned

GroupGenotypingMethod: 47 original patients with an NCL phenotype but no variant in one of the 5 tested loci were subjected to CLN5 genotyping. PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. 10 patients were identified as harboring CLN5 variants. 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.

GroupAddInfo: N/A

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

ExperimentName: Wild-type Prph2 localizes to mouse rod outer segments.

TissueExpression: photoreceptor outer segment layer (UBERON:0003926)

ExpressionEvidence: Western blotting with an anti-Prph2 antibody confirms that Prph2 is present in retinal outer segments and exists a a dimer (Fig. 2), although other control tissues are absent.

ExperimentName: AAV8-Nr2e3 rescue of rd7/rd7 mice

RescueModel: Mus musculus

GeneAlteration: Rescue was performed by subretinal injection of AAV8-Nr2e3 (or no treatment) into rd7/rd7 mice with homozygous disruption of endogenous Nr2e3

RescueVariant: No variant form of Nr2e3 was studied in this rescue experiment.

RescuePhenotype: The rescued phenotype is retinal spots in the fundus (Figure 3).

RescueMethod: This rescue model has introduction of the virally packaged mouse wild-type Nr2e3 gene.

RescueEvidence: Subretinal administration of the gene results in considerable improvement of the retinal spots in the fundus compared with untreated eyes 3 months post-injection (Figure 3).

ModelVariant: The model harbors homozygous out-of-frame deletion of 380 bp within the coding region of Nr2e3.

PMID: 33531964

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

PMID: 12515581

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#: Hejtmancik_2008_Family_55001_Proband, sex and age not specified, family origin described as American of European ancestry

CasePresentingHPOs: Snowflake vitreoretinal degeneration HP:0011533, Corneal guttata HP:0012038, Presenile cataracts HP:0007819, Abnormal vitreous humor morphology HP:0004327, Retinal detachment HP:0000541

CaseHPOFreeText: All family members have been diagnosed with Snowflake vitreoretinal degeneration between the ages of 12 and 85 years of age. Please note that detailed phenotypes were found in PMID: 14644728, and included fibrillar vitreous degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Orofacial features, early-onset hearing loss, and arthritis were absent.

CasePreviousTesting: The proband was previously subjected to linkage analysis mapping the causal locus to chromosome 2 (PMID: 15557460).

CaseMethod1: linkage analysis

CaseMethod2: Sanger sequencing of KCNJ13, COL4A3, SLC19A3, DNER, SLC17, 16A14, LOC646839, CAB39, PSMD1, ARMC9, NCL, PTMA, PDE6D, COPS7B, ECEL1, EFHD1, TNRC15, ATG16L1, SAG, USP40, and CENTG2

CaseGenotypingMethod: The family was previously genotyped by linkage analysis mapping the causal locus to chromosome 2 (PMID: 15557460), followed by Sanger sequencing of KCNJ13, COL4A3, SLC19A3, DNER, SLC17, 16A14, LOC646839, CAB39, PSMD1, ARMC9, NCL, PTMA, PDE6D, COPS7B, ECEL1, EFHD1, TNRC15, ATG16L1, SAG, USP40, and CENTG2.

Variant: The individual harbors the NM_002242.4(KCNJ13):c.484C>T (p.Arg162Trp) variant in the heterozygous state.

ClinVar: 6585

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.0000008536 (1 / 1,171,470) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr2-232768790-G-A?dataset=gnomad_r4

VariantEvidence:NM_002242.4(KCNJ13):c.484C>T (p.Arg162Trp) is a missense variant that has functional evidence of electrophysiological abnormalities and loss of sensitivity to different K+ concentrations, when exogenously expressed in CHO cells (Figure 2).

CaseAddInfo: The proband's family includes 12 other affected individuals carrying the variant, and 14 unaffected individuals (as well as 4 unaffected spouses) without the variant.

CasePMIDs: PMID: 15557460, PMID: 14644728

PMID: 9888420

Gene: RBP4

HGNC: 9922

Disease: progressive retinal dystrophy due to retinol transport defect

MONDO: 0014060

InheritancePattern: autosomal recessive

Prevalence: RBP4-related cases have an estimated prevalence of less than 1 in 1,000,000 (https://www.orpha.net/en/disease/detail/352718?search=&mode=name)

Penetrance: RBP4 disease-causing variants appear to have complete penetrance in biallelic cases.

PMID: 18408187

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: Two dog models of Rpgr loss-of-function

NonHumanModel: Canis lupus familiaris

GeneAlteration: The two models have disruption of the dog Rpgr gene by the c.1028_1032del frameshift variant or the c.1084_1085del frameshift variant, respectively.

ModelPhenotype: Normal photoreceptors until young adulthood in one model, HP:0000546 (Retinal degeneration), Photoreceptor outer segment cell degeneration, HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0008275 (Abnormal light-adapted electroretinogram), relative sparing of cones in both models, HP:0000618 (Blindness)

HumanPhenotype: HP:0007642 (Congenital stationary night blindness), HP:0007994 (Peripheral visual field loss), HP:0000529 (Progressive visual loss), HP:0000365 (Hearing impairment), HP:0002205 (Recurrent respiratory infections), HP:0011109 (Chronic sinusitis), HP:0000388 (Otitis media), HP:0002837 (Recurrent bronchitis), HP:0012263 (Immotile cilia), HP:0005938 (Abnormal respiratory motile cilium morphology)

ModelEvidence: The two models have been well-characterized at the ocular level and exhibit ERG abnormalities (Fig. 4IB1-3) and degeneration of visual cells and outer segment disorganization, leading to end-stage retinal disease (Fig.4IIE-4IIH). These phenotypes are consistent with human patient features such as night blindness, central visual field loss, and peripheral visual field loss.

ModelVariant: The models study naturally occurring variants that do not have equivalent / orthologous variants reported in human patients.

ExperimentName: Naturally occurring bbs-7 loss-of-function C. elegans model

NonHumanModel: C. elegans

GeneAlteration: The model animals harbor a naturally occurring homozygous nonsense variant at nucleotide 2899 within the bbs-7 locus.

ModelPhenotype: short cilia, defective chemotaxis, defective intraflagellar transport, IFT mislocalization

HumanPhenotype: HP:0001956 (Truncal obesity), HP:0000618 (Blindness), HP:0001249 (Intellectual disability), HP:0001631 (Atrial septal defect), HP:0001640 (Cardiomegaly), HP:0100598 (Pulmonary edema), HP:0012584 (Bilateral renal hypoplasia), HP:0004719 (Hyperechogenic kidneys), HP:0003774 (Stage 5 chronic kidney disease), HP:0000580 (Pigmentary retinopathy), HP:0000648 (Optic atrophy), HP:0008043 (Retinal arteriolar constriction), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007754 (Macular dystrophy)

ModelEvidence: This is a naturally occurring C. elegans model of biallelic bbs-7 disruption. The mutant animals exhibit reduced chemotaxis (dependent on two chemosensory neurons, Figure 2E), shorter cilia (Figure 3), defective localization of IFT particles (Figure 4), and reduced intraflagellar transport (Figure 5). Rescue of chemotaxis with expression of the wild-type C. elegans bbs-7 gene directly linked the defect with bbs-7 (Figure 2E).

ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied a naturally occurring and apparent null variant disrupting bbs-7 expression.

PMID: 15231740

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.

PMID: 16670814

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.

PMID: 29947567

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 87 with choroidal involvement

MONDO: 0032873

InheritancePattern: Autosomal Dominant

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 dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.

Penetrance: Incomplete penetrance, estimated at 80%

FamilyLabel: Gliem_2015_Family_2

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

FamilyHPOFreeText: Onset of symptoms in the early fifth or sixth decade of life, with either dark adaptation problems, metamorphopsia, or visual loss being the first symptoms, central and midperipheral atrophy, central fibrosis. Some affected family members were largely asymptomatic into the 6th decade of life, but had central retinal drusen. Choroidal neovascularization was observed in some family members and appeared to be a driver of vision loss.

FamilyNotHPOs: HP:0000662 (Nyctalopia)

FamilyNotHPOFreeText: Dark adaptation problems, early onset of symptoms

CountryOrigin: Germany

Family#PreviousTesting: N/A

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

Affected: 6

Unaffected: 2

Segregations: 12

PublishedLOD: N/A

eLOD: 2.1

AddSegregationInfo: N/A

ProbandLabel: Gliem_2000_Family_2_patient_V.1

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

CAID: CA411540365

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: 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.

FamilyPMIDs: PMID:25390527

Case: Gliem_2000_Family_3_patient_III.5, male, country of origin Germany, onset at 31 years of age

DiseaseAssertion: Sorsby's fundus dystrophy

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

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy), HP:0007737 (Bone spicule pigmentation of the retina),

CaseHPOFreeText: Relatively early presentation at age 31 with nyctalopia and prolonged dark adaptation. Evaluation at age 56 showed widespread central and peripheral atrophy, central fibrosis, and reduced choroidal thickness.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

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

GenotypingMethod: Sanger sequencing of PCR products from the TIMP3 and RP1L1 genes

PreviouslyPublished: N/A

SupplementalData: N/A

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

CAID: CA411540149

gnomAD: Variant is absent from gnomAD.

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

Case#: Riazuddin_2006_61074_patient_10, male, age 25 years at time of study, Pakistani family origin from remote Punjab province

CasePresentingHPOs: HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: The proband and her affected family members have been diagnosed with autosomal recessive retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage analysis, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33.

CaseMethod1: Genome-wide linkage analysis

CaseMethod2: Sanger sequencing of the candidate gene PDE6A

CaseGenotypingMethod: Genome-wide linkage analysis was initially performed on multiple families, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33. Sanger sequencing was then performed on PCR products of exons and flanking regions from the PDE6A candidate locus.

Variant: The affected members of Family 61074 harbor the NM_000440.3(PDE6A):c.1408-2A>G variant in the homozygous state.

ClinVar: 225119

gnomAD: This variant is present in gnomAD v2.1.1 at a frequency of 0.00003266 (1/30616 with no homozygotes) in the South Asian population https://gnomad.broadinstitute.org/variant/5-149276341-T-C

VariantEvidence: NM_000440.3(PDE6A):c.1408-2A>G is a variant disrupting a splice acceptor site in intron 10 that is predicted to result in exon 11 skipping, truncating 22 amino acids (~3%) of the protein product.

CaseAddInfo: The patient is from a family with consanguineous unions.

CasePMIDs: N/A

Case#: Riazuddin_2006_61021_patient_12, female, age 33 years at time of study, Pakistani family origin from remote Punjab province

CasePresentingHPOs: HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: The proband and her affected family members have been diagnosed with autosomal recessive retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage analysis, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33.

CaseMethod1: Genome-wide linkage analysis

CaseMethod2: Sanger sequencing of the candidate gene PDE6A

CaseGenotypingMethod: Genome-wide linkage analysis was initially performed on multiple families, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33. Sanger sequencing was then performed on PCR products of exons and flanking regions from the PDE6A candidate locus.

Variant: The affected members of Family 61021 harbor the NM_000440.3:c.2098dup (p.Tyr700LeufsTer21) variant in the homozygous state.

CAID: CA2573332091

gnomAD: This variant is absent from gnomAD v2.1.1.

VariantEvidence: NM_000440.3:c.2098dup (p.Tyr700LeufsTer21) is a frameshift variant in exon 17 of 22 that is predicted to trigger nonsense-mediated decay or at least to truncate ~19% of the protein product.

CaseAddInfo: The patient is from a family with consanguineous unions.

CasePMIDs: N/A

PMID: 17110911

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#: Fu_2013_Patient_4263_1, male, age 9 at time of report, family origin reported to be Chinese

CasePresentingHPOs: HP:0030534 (Abnormal best corrected visual acuity test), HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0007984 (Electronegative electroretinogram), HP:0410280 (Pediatric onset)

CaseHPOFreeText: The proband was initially diagnosed with retinitis pigmentosa with an autosomal recessive pattern of inheritance, and subsequently re-diagnosed with cone-rod dystrophy with early-onset retinal dystrophy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was initially genotyped by next-generation sequencing focusing on a panel of 163 known retinal disease genes.

CaseMethod1: Next-generation sequencing panel (163 genes)

CaseMethod2: Sanger sequencing of ADAM9

CaseGenotypingMethod: The proband was initially genotyped by next-generation sequencing focusing on a panel of 163 known retinal disease genes, followed by Sanger sequencing of ADAM9.

Variant: The proband harbors the NM_003816.3(ADAM9):c.1786C>T (p.Arg596Ter) variant in the homozygous state.

CAID: CA370746588

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

VariantEvidence: NM_003816.3(ADAM9):c.1786C>T (p.Arg596Ter) is a nonsense variant in exon 16 of 21, which is predicted to trigger NMD or to truncate the C-terminal ~27% of the protein product.

CaseAddInfo: The proband's parents are consanguineous and are each heterozygous for the variant, while his unaffected sister does not carry the variant.

CasePMIDs: N/A

PMID: 15148406

Gene: OPN1LW

HGNC: 9936

Disease: protan color blindness

MONDO: 0010565

InheritancePattern: X-linked

Prevalence: The overall prevalence of protan color blindness is approximately 1% in males, which is higher than that of blue cone monochromacy (~1 in 100,000, PMID: 35759666).

Penetrance: Known disease-causing alleles appear to be almost completely penetrant in males (PMID: 21167193).

MM is a patient with replacement of the entire OPN1LW locus by an additional copy of OPN1MW. This proband cannot be scored due to the variant type, but might be used for Functional Alteration in Patient Cells?

PMID: 11520764

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.

PMID: 36109576

Gene: IMPG1

HGNC: 6055

Disease: vitelliform macular dystrophy 4

MONDO: 0014508

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.

Case#: Yzer_2006_Patient_20955, female, diagnosed in the weeks after birth, Dutch or Belgian family origin

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity), HP:0000563 (Keratoconus), HP:0001483 (Eye poking), HP:0008043 (Retinal arteriolar constriction), HP:0007814 (Retinal pigment epithelial mottling), HP:0007688 (Undetectable light- and dark-adapted electroretinogram)

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis. Retinal pigment epithelium mottling in the mid- and far periphery was minimal.

CaseNotHPOs: HP:0000662 (Nyctalopia), HP:0000613 (Photophobia), HP:0001098 (Abnormal fundus morphology), HP:0000543 (Optic disc pallor), HP:0030825 (Absent foveal reflex)

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

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

ClinVar: 98563

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

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

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

CasePMIDs: N/A

PMID: 32242237

Gene: IMPG1

HGNC: 6055

Disease: vitelliform macular dystrophy 4

MONDO: 0014508

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.

PMID: 22072986

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.

PMID: 11581183

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.

PMID: 19797195

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.

Case#: Lazar_2014_Family_MOL0430_Patient_1, male, age 31 at time of report, national origin in Israel, ethnicity listed as North African Jewish

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0030515 (Moderately reduced visual acuity), HP:0011003 (High myopia), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram), HP:0000613 (Photophobia), HP:0007703 (Abnormality of retinal pigmentation), HP:0008179 (Decreased Arden ratio of electrooculogram)

CaseHPOFreeText: The patient has been diagnosed with cone-rod dystrophy.

CaseNotHPOs: HP:0030480 (Abnormal timing of light-adapted flicker electroretinogram), HP:0030470 (Abnormal dark-adapted bright flash electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Whole exome sequencing of the proband

CaseMethod2: Confirmation by Sanger sequencing

CaseGenotypingMethod: The proband was genotyped by whole exome sequencing, followed by confirmation by Sanger sequencing.

Variant: The proband harbors the NM_000180.4(GUCY2D):c.2538G>C (p.Lys846Asn) variant in the heterozygous state.

ClinVar: 812329

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.4(GUCY2D):c.2538G>C (p.Lys846Asn) is a missense variant located within the coiled-coil domain that mediates dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565). Cases from this family may be less severely affected, possibly similar to a reported variant at codon 849 (PMID: 26298565).

CaseAddInfo: The proband is an isolated case without family member phenotypes and genotypes available.

CasePMIDs: N/A

Case#: Lazar_2014_Family_MOL0508_Patient_III:1, female, age 25 at time of report, national origin in Israel, ethnicity listed as Ashkenazi Jewish

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0030515 (Moderately reduced visual acuity), HP:0011003 (High myopia), HP:0000552 (Tritanomaly), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram), HP:0030500 (Yellow/white lesions of the macula), HP:0025158 (Hyperautofluorescent retinal lesion)

CaseHPOFreeText: The patient has been diagnosed with maculopathy and cone dystrophy.

CaseNotHPOs: HP:0030480 (Abnormal timing of light-adapted flicker electroretinogram), HP:0030470 (Abnormal dark-adapted bright flash electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Whole exome sequencing

CaseMethod2: Confirmation by Sanger sequencing

CaseGenotypingMethod: The proband was genotyped by whole exome sequencing, followed by confirmation by Sanger sequencing.

Variant: The proband harbors the NM_000180.4(GUCY2D):c.2521G>A (p.Glu841Lys) variant in the heterozygous state.

ClinVar: 812328

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.4(GUCY2D):c.2521G>A (p.Glu841Lys) is a missense variant located within the coiled-coil domain that mediates dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565). Cases from this family may be less severely affected, possibly similar to a reported variant at codon 849 (PMID: 26298565).

CaseAddInfo: The proband is a member of a family with an affected mother who was not genotyped.

CasePMIDs: N/A

Case#: Stunkel_2018_Patient_2, male, age 9 at diagnosis with congenital night blindness, age 14 at time of report, ethnic origin not mentioned

CasePresentingHPOs: HP:0003621 (Juvenile onset), HP:0000662 (Nyctalopia), HP:0030474 (Undetectable dark-adapted electroretinogram), HP:0007987 (Progressive visual field defects), HP:0001133 (Constriction of peripheral visual field), HP:0002527 (Falls), HP:0030329 (Retinal thinning)

CaseHPOFreeText: Minor color vision errors were detected by D15 testing.

CaseNotHPOs: HP:0003593 (Infantile onset), HP:0030534 (Abnormal best corrected visual acuity test), HP:0030586 (Abnormal Ishihara plate test), HP:0000539 (Abnormality of refraction), HP:0000639 (Nystagmus), HP:0000486 (Strabismus), HP:0007663 (Reduced visual acuity), HP:0030473 (Abnormal light-adapted flicker electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Negative screening for variants in NYX, CACNA1F, RHO, or TRPM1

CaseMethod1: Whole exome sequencing

CaseMethod2: N/A

CaseGenotypingMethod: This individual was initially subjected to screening for variants in NYX, CACNA1F, RHO, or TRPM1, with negative results. Whole exome sequencing then detected 2 variants in GUCY2D.

Variant: The individual is compound heterozygous for the NM_000180.4(GUCY2D):c.247C>T (p.Arg83Cys) and NM_000180.4(GUCY2D):c.1633C>T (p.Gln545Ter) variants.

CAID: CA397943039

ClinVar: 689384

gnomAD: Neither variant was found in gnomAD.

VariantEvidence: Evidence supporting the pathogenicity of the NM_000180.4(GUCY2D):c.247C>T (p.Arg83Cys) variant is limited to computational prediction. NM_000180.4(GUCY2D):c.1633C>T (p.Gln545Ter) is a nonsense variant in exon 7 predicted to trigger NMD or to at least disrupt ~51% of the protein product through truncation.

CaseAddInfo: The mother of Patient 2 has been found to carry one of the variants in a heterozygous state, consistent with the expected segregation pattern.

CasePMIDs: N/A

PMID: 26216056

Gene: IFT140

HGNC: 29077

Disease: polycystic kidney disease

MONDO: 0020642

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of polycystic kidney disease is between 1 in 400 and 1 in 1,000 individuals (PMID: 30523303).

Penetrance: Disease caused by monoallelic IFT140 variants is incompletely penetrant.

ExperimentName: The eclipse / els zebrafish mutant harbors a missense variant in the PDE6C ortholog pde6alpha'.

NonHumanModel: Danio rerio

GeneAlteration: The model animals are homozygous for a missense variant p.Met175Arg.

ModelPhenotype: HP:0008020 (cone dystrophy), HP:0030465 (Undetectable light-adapted electroretinogram), normal dark-adapted ERG, rapid and progressive elimination of cone photoreceptors from adult retinas

HumanPhenotype: HP:0030465 (Undetectable light-adapted electroretinogram), HP:0030534 (Abnormal best corrected visual acuity test), HP:0000551 (Color vision defect), HP:0000613 (Photophobia), HP:0000639 (Nystagmus), HP:0007401 (Macular atrophy), HP:0000545 (Myopia)

ModelEvidence: This is a naturally occurring zebrafish model that matches the mode of inheritance from the human patients and exhibits lack of light-adapted ERG responses (Figures 1K, 1M) and normal dark-adapted ERG responses. Optokinetic responses mediated by rod function were normal, while those mediated by cone function were absent (Figure 4). The mice also exhibit rapid and progressive loss of cone photoreceptors from retinal sections (Figures 1G, 1I) and abnormal shape of the photoreceptor outer segment (Figure 1C). Rod markers are maintained while cone markers are absent from adult animals (Figure 4).

ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied a naturally occurring variant disrupting the PDE6alpha' locus orthologous to human PDE6C.

PMID: 15728307

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: 22815753

GeneName: GNAT2

HGNC: 4394

Disease: achromatopsia 4

MonDO ID: MONDO_0013465

Inheritance: autosomal recessive

PMID: 12766038

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.

Wild-type Prph2 (referred to as RDS) co-localizes with ROM-1 protein within the rim regions of outer segment discs.

PMID: 1684223

Gene: PRPH2

HGNC: 9942

Disease: retinitis pigmentosa 7

MONDO: 0011974

InheritancePattern: semi-dominant

Prevalence: The incidence of PRPH2-related cases among inherited retinal dystrophies is reported to range from 3.5% in North America to 10.3% in France (PMID: 36010202).

Penetrance: The penetrance among biallelic cases appears to be complete, while the monoallelic cases exhibit incomplete penetrance (PMID: 36609934).

FamilyLabel: Lebrun_2009_Family_2

Family#PresentingHPOs: HP:0001251 (Ataxia), HP:0001250 (Seizure), HP:0000750 (Delayed speech and language development), HP:0011463 (Childhood onset),

Family#PresentingHPOFreeText: Ataxia and delay in speech development were the first presenting phenotypes, with onset between ages 2 and 3. Epileptic seizures first occurred at age 4.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: N/A

Ethnicity: Family is of Afghan ethnic origin.

Race: N/A

Family#PreviousTesting: The extent of previous testing within this family is unclear.

Family#Method1: N/A

Family#Method2: N/A

Family#GenotypingMethod: CLN5 mRNA was reverse transcribed, PCR-amplified, and subjected to Sanger sequencing. This process was performed for both affected and control individuals (parents).

Affected: 2

Unaffected: 2

Segregations: 1 segregation is reported in the family.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Lebrun_2009_Patient_2

Variant: Both affected patients are homozygous for the NM_006493.4(CLN5):c.990G>T (p.Trp330Cys) variant, (although this variant is referred to in the article as c.1137G>T (p.Trp379Cys)).

ClinVar: 56530

gnomAD: The variant is reported to have a maximum allele frequency of 0.00006484 (in the European non-Finnish population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77575017-G-T

FamilyAddInfo: The family is consanguineous, as parents are described as first degree cousins. Parents were heterozygous for the variant. Family relationships between individuals were verified.

FamilyPMIDs: N/A

Case#: Khan_2019_proband_1, male, age 8 years at time of report, national origin reported as Emirati

CasePresentingHPOs: HP:0000613 (Photophobia), HP:0000545 (Myopia), HP:0000577 (Exotropia), HP:0007663 (Reduced visual acuity), HP:0410280 (Pediatric onset), HP:0025158 (Hyperautofluorescent retinal lesion), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)

CaseHPOFreeText: The patient has been diagnosed with childhood-onset rod-cone dystrophy with early macular involvement.

CaseNotHPOs: HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of a retinal dystrophy gene panel.

CaseMethod1: retinal dystrophy gene panel

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

CaseGenotypingMethod: Genotyping consisted of a retinal dystrophy gene panel followed by Sanger sequencing of the 19 exons of the IMPG2 gene.

Variant: The patient harbors the NM_016247.4(IMPG2):c.189dup (p.Gln64fs) variant in the homozygous state.

ClinVar: 978976

gnomAD: The variant was found in gnomAD v2.1.1.

VariantEvidence: NM_016247.4(IMPG2):c.189dup (p.Gln64fs) is a frameshift variant in exon 2 of 19 that is predicted to trigger NMD or to at least truncate the C-terminal 95% of the protein product.

CaseAddInfo: The family is consanguineous, with the parents being first cousins and heterozygous carriers of the variant.

CasePMIDs: N/A

PMID: 41513982

Gene: RNU4-2

HGNC: 10193

Disease: inherited retinal dystrophy

MONDO: 0019118

InheritancePattern: autosomal dominant

Prevalence: The prevelance of retinitis pigmentosa in general is between 1 in 750 and 1 in 9,000 individuals (PMID: 37108642). The proportion of those cases caused by RNU4-2 variants is not well known.

Penetrance: Penetrance appears to be incomplete, with family pedigrees including apparently unaffected carriers.

PMID: 10725384

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: 16223891

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

FamilyLabel: Manes_2013_Family_MTP327

Family#PresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0030469 (Abnormal dark-adapted electroretinogram, specifically reduced)

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with vitelliform macular dystrophy.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: The family is reportedly French.

Ethnicity: Not specifically described

Race: Not specifically described

Family#PreviousTesting: Previous genotyping included Sanger sequencing of BEST1 and PRPH2, followed by genome-wide scan using a 250K SNP Affymetrix array, which identified a shared 95.2 Mb haplotype on chromosome 6p12.1-q24.3 (encompassing 705 genes) in all affected family members. The candidate loci ELOVL4 and MCDR1 were then subjected to Sanger sequencing.

Family#Method1: Whole-exome sequencing of seven affected family members

Family#Method2: Sanger sequencing of IMPG1 to confirm the presence of the variant.

Family#GenotypingMethod: Whole-exome sequencing of seven affected family members was performed, followed by Sanger sequencing of IMPG1 to confirm the presence of the variant.

Affected: 8 genotyped

Unaffected: 4 genotyped

Segregations: 11 segregations are shown by the pedigree in Figure 1A.

PublishedLOD: 3.02 (for the D6S1622 marker on chromosome 6q13)

eLOD: N/A

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

ProbandLabel: Manes_2013_Family_MTP327_Proband

Variant: The affected family members harbor the NM_001563.4(IMPG1):c.713T>G (p.Leu238Arg) variant in the heterozygous state.

ClinVar ID: 162133

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

VariantEvidence: NM_001563.4(IMPG1):c.713T>G (p.Leu238Arg) is a missense site variant lacking evidence of a deleterious impact on the gene product.

FamilyAddInfo: The family's national origin has been reported as French. Age of onset ranged from 20 to 45 years.

FamilyPMIDs: N/A

ExperimentName: LRP5 interacts with SOST

InteractingGene: SOST (HGNC:13771)

InteractionType: Physical

InteractionMethod: Co-immunoprecipitation

InteractionEvidence: Immunoprecipitation of an exogenously expressed IgG-SOST fusion protein from conditioned medium pulled down the Myc-tagged soluble portion of LRP5 (and LRP6, but not control targets) (Fig. 3A). Subsequent experiments identified SOST as an LRP5/6 antagonist that attenuates canonical Wnt signaling through these receptors (Figure 4).

PMID: 28644393

Gene: IMPG1

HGNC: 6055

Disease: vitelliform macular dystrophy 4

MONDO: 0014508

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.

Case#: van_Huet_2014_Patient_H-II:6, female, age 17 years at time of onset, age 46 years at the time of report, national origin reported as Dutch

CasePresentingHPOs: Nyctalopia HP:0000662, HP:0011462 (Young adult onset), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0000518 (Cataract), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000550 (Undetectable electroretinogram), HP:0011510 (Drusen)

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 consisted of autozygosity mapping (PMID: 20673862).

CaseMethod1: Homozygosity mapping

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

CaseGenotypingMethod: Genotyping consisted of autozygosity mapping (PMID: 20673862) followed by Sanger sequencing of the 19 exons of the IMPG2 gene.

Variant: The affected family members harbor the NM_016247.4(IMPG2):c.513T>G (p.Tyr171Ter) and NM_016247.4(IMPG2):c.2716C>T (p.Arg906Ter) variants in the compound heterozygous state.

ClinVar: 191181, 3548

gnomAD: These two variants were not found in gnomAD v2.1.1.

VariantEvidence: The NM_016247.4(IMPG2):c.513T>G (p.Tyr171Ter) variant is a nonsense variant in exon 4 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 86% of the protein product. The NM_016247.4(IMPG2):c.2716C>T (p.Arg906Ter) variant is a nonsense variant in exon 13 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 27% of the protein product.

CaseAddInfo: The family is reportedly non-consanguineous, and the patient has a similarly affected sister with the same genotype. Segregation of the two variants has been demonstrated within the family.

CasePMIDs: PMID: 20673862

Case#: van_Huet_2014_Patient_B-II:1, female, in childhood at time of onset, age 66 at the time of report, national origin reported as Iraqi Jewish

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0011003 (High myopia), HP:0007663 (Reduced visual acuity), HP:0007787 (Posterior subcapsular cataract), HP:0100018 (Nuclear cataract), HP:0030856 (Posterior staphyloma), HP:0007401 (Macular 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), HP:0007688 (Undetectable light- and dark-adapted electroretinogram)

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.635C>G (p.Ser212Ter) variant in the homozygous state.

ClinVar: 3546

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

VariantEvidence: The NM_016247.4(IMPG2):c.635C>G (p.Ser212Ter) variant is a nonsense variant in exon 6 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 83% of the protein product.

CaseAddInfo: The family is reportedly consanguineous, with the parents being first cousins. The proband has two affected sisters who share the same genotype, and each parent is a heterozygous carrier.

CasePMIDs: PMID: 20673862

PMID: 1845973

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: 11062471

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.

PMID: 23372056

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.

Case#: Hughes_2012_CACD_Family_Proband, male, age not specified, origin listed as Northern Irish

CasePresentingHPOs: HP:0003581 (Adult onset), HP:0032037 (Mildly reduced visual acuity), HP:0007722 (Retinal pigment epithelial atrophy), HP:0000580 (Pigmentary retinopathy), HP:0030491 (Choriocapillaris atrophy), HP:0001105 (Retinal atrophy)

CaseHPOFreeText: The patient has been diagnosed with central areolar choroidal dystrophy. Onset was during the 30s or 40s, and the presenting symptom was mild loss of central vision.

CaseNotHPOs: HP:0000613 (Photophobia), HP:0000551 (Color vision defect), HP:0012511 (Temporal optic disc pallor)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Linkage analysis previously mapped the disease-causing variant to chr17p13 (PMID: 9733038, PMID: 8733141).

CaseMethod1: Custom sequence capture array (next-generation) focusing on the linkage region on chromosome 17p13 (146 genes), using DNA from the proband and pooled affected and control samples.

CaseMethod2: Confirmation by Sanger sequencing of exon 15.

CaseGenotypingMethod: The proband and family members were genotyped by a combination of linkage analysis within the large pedigree, custom sequence capture array focusing on 146 genes within the linkage region on chromosome 17p13, and Sanger-based confirmation within exon 15.

Variant: The proband harbors the NM_000180.4(GUCY2D):c.2798T>C (p.Val933Ala) variant in the heterozygous state.

ClinVar: 617917

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.4(GUCY2D):c.2798T>C (p.Val933Ala) is a missense variant located in exon 15, which is part of the catalytic domain rather than the coiled-coil domain that mediates dimerization. Other variants for this disease entity are located within the coiled-coil domain instead. Phenotypic differences between this case and those may reflect genotype-phenotype correlation or differences in mechanism.

CaseAddInfo: The proband is a member of a large family (from the second generation) with other affected genotype-positive members.

CasePMIDs: PMID: 9733038, PMID: 8733141

Case#: Georgiou_2024_Family_GC19393_Proband_P06, female, reported at age 14 years, family origin reported as from Pakistan

CasePresentingHPOs: HP:0011003 (High myopia), HP:0030555 (Best corrected visual acuity 0.2 LogMAR)

CaseHPOFreeText: BCVA began at 0.20 logMAR and progressed to 0.30 logMAR.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was by either next-generation sequencing panel, whole exome sequencing, or whole genome sequencing, but was unspecified.

CaseMethod1: NGS panel / WES / WGS

CaseMethod2: Sanger sequencing of RBP3

CaseGenotypingMethod: Previous genotyping by either next-generation sequencing panel, whole exome sequencing, or whole genome sequencing was followed by Sanger sequencing of RBP3.

Variant: The individual harbors the NM_002900.3(RBP3):c.160C>T (p.Gln54Ter) variant in the homozygous state.

ClinVar ID: 964958

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.0003184 (29 / 91094) in the South Asian population https://gnomad.broadinstitute.org/variant/10-47348644-C-T?dataset=gnomad_r4

VariantEvidence: NM_002900.3(RBP3):c.160C>T (p.Gln54Ter)) is a nonsense variant within exon 1 of 4 that is predicted to trigger nonsense-mediated decay.

CaseAddInfo: Potential consanguinity within the proband's family has not been commented on.

CasePMIDs: N/A

Case#: Fattahi_2014_Patient_40302, male, age not specified, ethnicity reported as Fars, national origin reported as Iranian

CasePresentingHPOs: HP:0001513 (Obesity), HP:0000510 (Rod-cone dystrophy), HP:0000545 (Myopia), HP:0001161 (Hand polydactyly), HP:0001829 (Foot polydactyly), HP:0000077 (Abnormality of the kidney), HP:0000026 (Male hypogonadism), HP:0002463 (Language impairment), HP:0000639 (Nystagmus), HP:0001627 (Abnormal heart morphology), HP:0000708 (Atypical behavior), HP:0002251 (Aganglionic megacolon), HP:0001156 (Brachydactyly), HP:0001511 (Intrauterine growth retardation)

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

CaseNotHPOs: HP:0000518 (Cataract), HP:0000662 (Nyctalopia), HP:0000486 (Strabismus), HP:0001328 (Specific learning disability)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of Sanger sequencing of the BBS1, BBS2, BBS10, BBS3, BBS4, BBS6, BBS9, and BBS12 genes.

CaseMethod1: Sanger sequencing of the BBS1, BBS2, BBS10, BBS3, BBS4, BBS6, BBS9, and BBS12 loci

CaseMethod2: Sanger sequencing of the BBS7 locus.

CaseGenotypingMethod: Genotyping was performed using Sanger sequencing of the BSB1, BBS2, BBS10, BBS3, BBS4, BBS6, BBS7, BBS9, and BBS12 genes.

Variant: The patient harbors the NM_018190.4:c.1342_1346del (p.Gln448Argfs*13) and NM_018190.4:c.1443T>A (p.Cys481Ter) variants in the compound heterozygous state.

CAID: CA2580617740, CA358058685

gnomAD: The NM_018190.4:c.1342_1346del (p.Gln448Argfs*13) and NM_018190.4:c.1443T>A (p.Cys481Ter) variants were not found in gnomAD v2.1.1.

VariantEvidence: NM_018190.4:c.1342_1346del (p.Gln448Argfs*13) is a frameshift variant in exon 13 of 18 that is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 37% of the protein product. NM_018190.4:c.1443T>A (p.Cys481Ter) is a nonsense variant in exon 14 of 18 that is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 33% of the protein product..

CaseAddInfo: Consanguinity is not present in the proband's family.

CasePMIDs: N/A

PMID: 9006347

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