PMID: 18849587

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.

PMID: 25711638

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.

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: next-generation sequencing

CaseMethod2: Sanger sequencing of PRPF4

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

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

ClinVar ID: 143058

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

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

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

CasePMIDs: N/A

ExperimentName: Retinal dystrophy in dogs is caused by Rpe65 loss of function.

NonHumanModel: Canis familiaris

GeneAlteration: Swedish Briard / Briard Beagle dogs exhibit a biallelic 485delAAGA variant in the RPE65 locus that triggers a frameshift predicted to disrupt ~71% of the protein product.

ModelPhenotype: HP:0007642 (Congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0000618 (Blindness), HP:0007703 (Abnormality of retinal pigmentation), HP:0000556 (Retinal dystrophy), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0007984 (Electronegative electroretinogram), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram)

HumanPhenotype: HP:0000662 (Nyctalopia), HP:0000529 (Progressive visual loss), HP:0000618 (Blindness), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram), HP:0030474 (Undetectable dark-adapted electroretinogram)

ModelEvidence: The model system recapitulates the human phenotype in that the dogs exhibit severe vision loss (Table 1 in PMID: 2804031, describing the same animal model), structural abnormalities of the RPE (PMID: 7851218, studying the same animal model), and similar ERG abnormalities (Figures 2 and 3 in PMID: 2804031). Similar to the human patient families, the heterozygous individuals are unaffected (Figure 1 in this publication).

ModelVariant: The dogs harbor a spontaneously occurring frameshift variant in exon 5 of 14 (485delAAGA), rather than a targeted mutation equivalent to a particular human patient variant.

Note: No variants found in PRPF4 in affected patients.

ExperimentName: Rpe65 homozygous knockout abolishes rod photoreceptor function and disrupts RPE metabolism in mice.

NonHumanModel: Mus musculus

GeneAlteration: Rpe65 homozygous knockout was generated by replacing the 5' flanking region and the first three exons of Rpe65 with a PGK-Neo cassette.

ModelPhenotype: HP:0000479 (Abnormal retinal morphology), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0007984 (Electronegative 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 model system recapitulates the human phenotype in that the mice exhibit progressive onset of abnormalities in retinal morphology (specifically photoreceptor outer segment loss, Figures 2a-2e), accompanied by reduced responses in dark-adapted (Figure 4) but not light-adapted (Figure 5) ERG. These ERG results are characteristic of abolished rod function. The mice also recapitulate the molecular features of the human patients in that retinal esters accumulate in the retinal pigment epithelium of the mice (HPLC data in Figures 8a-8c).

ModelVariant: The model disrupts the entire Rpe65 locus rather than introducing a mutation equivalent to a human patient variant.

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

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

CaseHPOFreeText: ERG with absent oscillatory-potential wavelets

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

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing of PCR amplified exons from NYX

CaseMethod2: N/A

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

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

ClinVar: 99843

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

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

CaseAddInfo: Phenotype information is found in PMID: 12397430.

CasePMIDs: 12397430

PMID: 38206458

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.

PMID: 1986774

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).

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

ExperimentName: Wild-type Prph2 expression in the developing mouse retina begins on day postnatal day 6.

TissueExpression: photoreceptor outer segment layer (UBERON:0003926)

ExpressionEvidence: Immunohistochemistry indicates that wild-type Prph2 expression in the developing mouse retina begins on day postnatal day 6 (Figure 3C). This time point coincides with the timing of the formation of the photoreceptor outer segment discs, and is consistent with a proposed function of PRPH2 as an adhesion molecule that acts to stabilize the outer segment discs.

PMID: 24148654

GeneName: GNAT2

HGNC: 4394

Disease: achromatopsia 4

MonDO ID: MONDO_0013465

Inheritance: autosomal recessive

ExperimentName: PRPF4 physically interacts with PRPF3.

InteractingGene: PRPF3 (HGNC:17348)

InteractionType: Physical

InteractionMethod: Co-immunoprecipitation

InteractionEvidence: Immunoprecipitation of endogenous PRPF3 from HeLa cell nuclear extracts pulled down PRPF4 (Figures 5 and 6).

Selection B- Gene function is consistent with phenotype.

ExperimentName: OPN1LW encodes a long-wave-sensitive opsin and can rescue cone-mediated function when subretinally injected in Opn1mw−/−/Opn1sw−/− mice.

GOterm: GO:0007602 (phototransduction)

FunctionalEvidence: Subretinal injection of AAV carrying the OPN1LW gene encoding human L-opsin into mice at age 2 months or younger promoted cone outer segment regeneration () and rescued cone functions such as the b-wave amplitude of the long wavelength-mediated electroretinogram response (Figures 2A, 2B, 4D) and visually guided behavior (Figure 4E).

FunctionalHPO: Protanopia HP:0011522

PMID: 30239781

Gene: GUCY2D

HGNC: 4689

Disease: Leber congenital amaurosis 1

MONDO: 0008764

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 GUCY2D variants is between 10% and 20% (PMID: 10951519). Thus, the prevalence of Leber congenital amaurosis 1 is between 1 in 165,000 and 1 in 1,000,000.

Penetrance: Fully penetrant, with onset in neonates or in infancy

FamilyLabel: Morimura_1998_Family_7828

FamilyPresentingHPOs: HP:0000546 (Retinal degeneration)

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

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: The Dominican Republic

Ethnicity: Not mentioned

Race: Not mentioned

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

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

Affected: 5

Unaffected: 5

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

PublishedLOD: N/A

eLOD: 3.03

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

ProbandLabel: Morimura_1998_Patient_III-4

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

ClinVar: 13118, 98831

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

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

FamilyPMIDs: N/A

ExperimentName: "Prpf4 silencing in zebrafish causes defects in visual function."

NonHumanModel: Danio rerio

GeneAlteration: The model animals have been subjected to morpholino-based knockdown of Prpf4, the zebrafish ortholog of human PRPF4.

ModelPhenotype: Nystagmus HP:0000639, Abnormality of ocular smooth pursuit HP:0000617

HumanPhenotype: Constriction of peripheral visual field HP:0001133, Reduced visual acuity HP:0007663,, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654. Retinal degeneration HP:0000546, Macular degeneration HP:0000608, Optic disc pallor HP:0000543, Attenuation of retinal blood vessels HP:0007843, Pigmentary retinopathy HP:0000580

ModelEvidence: Morpholino-based incomplete knockdown of the Prpf4 gene circumvents the lethality of complete silencing and causes optokinetic nystagmus with a significantly reduced number of saccades (Fig. 5B, 5C, 5D). Immunohistochemistry showed that retinal morphology showed mostly normal retinal layering but decreased rhodopsin staining in the photoreceptor cell layer (Figs. 5E–5H). Photoreceptor outer segments were primarily affected, but with unaffected cell body morphology (Figs. 5I and 5J). This phenotype was a complete match for the zebrafish with Prpf31 loss/. Semi-quantitative RT–PCR analysis of the RP-relevant transcripts opn1lw1, opn1mw1, gnat2, irx6a, rx3, crx and rhodopsin as well as the controls gapdh and lsm7 showed a very similar pattern of down-regulation in both Prpf31- and Prpf4-deficient animals (Fig. 5W). The phenotype was dose-dependent and could be rescued by co-injection of Prpf4 mRNA (Fig. S2).

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

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Linkage mapping

CaseMethod2: Sanger sequencing

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

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

ClinVar: 98619

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

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

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

CasePMIDs: PMID: 1355560, PMID: 8301646

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Homozygosity mapping within the family

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

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

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

ClinVar: 538

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

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

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of autozygosity mapping.

CaseMethod1: Homozygosity mapping

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

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

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

ClinVar: 3549

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

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

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

CasePMIDs: N/A

PMID: 23105016

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.

PMID: 32737437

autosomal dominant case

PMID: 11971870

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

ExperimentName: Rescue of mouse Gucy2e homozygous knockout model by AAV-borne human GUCY2D transgene

NonHumanModel: Mus musculus

GeneAlteration: The mouse Gucy2e gene was disrupted by the introduction of a neomycin-resistance gene cassette into exon 5, resulting in a truncated protein lacking its transmembrane domain (PMID: 10407028). The effects of this knockout were studied in the homozygous state.

RescueVariant: Rescue was performed with the wild-type human GUCY2D and mouse Gucy2e genes but not with a patient-derived variant.

RescuePhenotype: HP:0030465 (Undetectable light-adapted electroretinogram), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0000479 (Abnormal retinal morphology), HP:0008020 (Cone dystrophy)

RescueMethod: Human GUCY2D or mouse Gucy2e was cloned into an overexpression construct under the control of the human rhodopsin kinase promoter and packaged into adeno-associated (AAV2/8) viral particles for 2 subretinal injections on postnatal day 10. Efficacy was measured by ERG recordings every two weeks.

RescueEvidence: Treatment with the human GUCY2D gene restored proper localization of alpha-transducin (Figs. 3a-3b), which was first reported by PMID: 15623748 to be abnormal in this model. Treatment corrected the defect in scotopic b-wave amplitude by 65-100% (Figs. 4a-4b). Cone amplitude was corrected from 20% of wild-type to 65% of wild-type (Fig. 4c). Similar results were obtained with the mouse Gucy2e transgene (Fig. 5). Head-tracking behavior (measure of visual acuity and contrast sensitivity) was fully corrected by treatment (Fig. 6). Moderate cone preservation was also demonstrated by normalization of alpha-transducin staining, showing a 20% increase in cone numbers relative to the untreated control (Fig. 7r).

ModelVariant: The mouse model disrupts the expression of the endogenous GC1 protein product but does not feature knock-in of a variant from a human patient.

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

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

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

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

CaseNotHPOFreeText: N/A

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

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

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

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

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

ClinVar: 866129

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

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

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

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

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

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

ClinVar: 453243

gnomAD: The variant was not found in gnomAD.

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

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

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

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

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

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

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

CaseNotHPOFreeText: N/A

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

CaseMethod1: targeted exome or whole exome sequencing

CaseMethod2: Sanger sequencing of OPN1LW

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

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

CAID: CA2695237718

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

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

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

CasePMIDs: N/A

PMID: 36206764

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.

FamilyLabel: Gliem_2015_Family_3

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

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

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Germany

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

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

Affected: 2

Unaffected: 2

Segregations: 2

PublishedLOD: N/A

eLOD: N/A

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

ProbandLabel: Gliem_2000_Family_3_patient_III.5

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

CAID: CA411540149

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

PMID: 11115851

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.

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

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

CaseHPOFreeText: The proband additionally exhibits slow ideation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: targeted exome sequencing

CaseMethod2: Sanger sequencing of BBS1

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

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

ClinVar ID: 12143, 981241

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

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

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

CasePMIDs: N/A

ExperimentName: Knockout mouse model of Impg1

NonHumanModel: Mus musculus

GeneAlteration: The mouse model harbors a deletion of exon 6, resulting in disruption of reading frame and loss of Impg1 protein either in the heterozygous or homozygous state.

ModelPhenotype: HP:0025158 (Hyperautofluorescent retinal lesion), HP:0000512 (Abnormal electroretinogram, specifically attenuated responses), HP:0030609 (Photoreceptor layer loss on macular OCT, described as degeneration with loss of 11-cis-retinal signal), HP:0007703 (Abnormality of retinal pigmentation, specifically disruption of RPE cells and the IPM)

HumanPhenotype: HP:0007754 (Macular dystrophy), HP:0007769 (Peripheral retinal degeneration), HP:0032037 (Mildly reduced visual acuity, progressive), HP:0008179 (Decreased Arden ratio of electrooculogram), HP:0030505 (Nummular pigmentation of the fundus)

ModelEvidence: The model exhibits phenotypes consistent with a critical role of Impg1 in photoreceptor maintenance. Phenotypes included hyperpigmented and sometimes autofluorescent subretinal deposits that were present at 9 months of age (Figure 2B) and increased by 14 months of age (Figure 2C) that were localized between the photoreceptor outer segment and the RPE (Figure 2D). Some images showed nummular pigmentation of the fundus (Figure 2E). Interestingly, attenuation of ERG response was first noted at 9 months and pronounced at 14 months (Figure 3A), which is consistent with the findings from an independent mouse model that showed less dramatic findings at earlier 5 month and 8 month time points (PMID: 32265257). Scotopic ERG was more affected than photopic ERG (Figure 3B). Retinal thickness was also reduced in the outer layer relative to the inner layer (Figure 3C). Retinoid generation was also progressively abnormal (Figure 4), indicating that photoreceptors might be lost. The IPM was also disorganized at 14 months (Figure 5), with cellular material accumulating in the IPM consistent with cell death (Figure 6).

ModelVariant: The model harbors a knockout allele disrupting Impg1, rather than a specific variant from a human patient.

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

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

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

CaseNotHPOs: HP:0007769 (Peripheral retinal degeneration)

CaseNotHPOFreeText: N/A

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

CaseMethod1: homozygosity mapping

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

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

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

ClinVar ID: 8763

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

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

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

CasePMIDs: N/A

PMID: 34287097

Gene: OPN1LW

HGNC: 9936

Disease: red color blindness

MONDO: MONDO:0010565

InheritancePattern: X-linked

Prevalence: Protanomaly and protanopia are common disorders with peak frequencies (among the males of certain populations) of 1.94% and 1.28%, respectively (PMID: 30258865).

Penetrance: The penetrance of the phenotype among hemizygous cases appears to be complete or near-complete.

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

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

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

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

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

ClinVar: 9357

gnomAD: The variant was not found in gnomAD.

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

CaseAddInfo: N/A

CasePMIDs: N/A

PMID: 28549772

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: 12960219

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: 25920554

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: 29706353

Gene: IFT140

HGNC: 29077

Disease: Short-rib thoracic dysplasia 9 with or without polydactyly

MONDO: 0009964

InheritancePattern: autosomal recessive

Prevalence: Within the lumped disease entity for this curation, the most prevalent form may be retinitis pigmentosa. The prevalence of Saldino-Mainzer syndrome (one of the synonyms of Short-rib thoracic dysplasia 9) is less than 1 in 1,000,000. The prevalence of Leber congenital amaurosis cases caused by IFT140 variants (PMID: 26216056) is calculated to be less than 1 in 3,000,000. Although IFT140 variants are estimated to be responsible for less than 2% of RP, the prevalence of the overall disorder at 1 in 3,000 or 1 in 4,000 means the frequency of these cases could potentially be higher than 1 in 1,000,000.

Penetrance: Known variants for this lumped disease entity appear to be completely penetrant, with highly variable phenotypes and age of onset. On the other hand, the split disease entity caused by monoallelic IFT140 variants appears to have incomplete penetrance.

PMID: 33805381

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: 34793838

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: 20038682

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.

FamilyLabel: Olivier_2021_Family_A

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

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

FamilyNotHPOs: N/A

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

CountryOrigin: The family is reportedly French.

Ethnicity: Not specifically described

Race: N/A

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

Family#Method1: whole-exome sequencing

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

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

Affected: 10 genotyped

Unaffected: 4 genotyped

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

PublishedLOD: N/A

eLOD: 2.7

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

ProbandLabel: Olivier_2021_Family_Proband_IV-8

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

CAID: CA3898050

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

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

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

FamilyPMIDs: N/A

PMID: 16632484

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: homozygosity mapping and exome sequencing

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

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

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

ClinVar: 30331

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

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

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

CasePMIDs: N/A

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140

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

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

ClinVar: 31683, 31680

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

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

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

CasePMIDs: N/A

ExperimentName: BBS7 interacts with other components of the BBSome.

InteractingGene: BBS4 (HGNC:969)

InteractionType: Physical

InteractionMethod: co-immunoprecipitation

InteractionEvidence: Antibody-based isolation of BBS4 results in co-purification of BBS7, as well as BBS1, BBS2, BBS5, BBS8, and BBS9 in stoichiometric quantities. The co-purifying proteins are shown separated by gel electrophoresis in Figure 1F and were identified and quantified by mass spectrometry in Table S1. All 8 proteins are encoded by genes linked to Bardet-Biedl syndrome.

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: whole exome sequencing

CaseMethod2: Sanger sequencing of OPN1LW

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

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

CAID: CA2739290587

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

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

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: N/A

CaseMethod2: N/A

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

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

ClinVar: 2564 (homozygous)

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

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

CaseAddInfo: N/A

CasePMIDs: N/A

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

DiseaseAssertion: Sorsby's fundus dystrophy

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

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

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

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

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

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

GenotypingMethod: Mutational screening of TIMP3 by bidirectional Sanger sequencing

PreviouslyPublished: N/A

SupplementalData: N/A

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

CAID: CA411540222

gnomAD: Variant is absent from gnomAD.

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

PMID: 30996589

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

DiseaseAssertion: Sorsby's fundus dystrophy

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

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

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

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: Rheumatological exam and renal function were both normal.

CasePreviousTesting: Phenotypic characterization only

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

PreviouslyPublished: PMID:11734514

SupplementalData: N/A

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

ClinVar: 12680

gnomAD: Variant is absent from gnomAD.

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

PMID: 11104772

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: 16814585

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: 12134079

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

Selection B - Gene function is consistent with phenotype.

Title: LRP5 is a canonical Wnt signaling pathway co-receptor.

GOterm: GO:0060070 (canonical Wnt signaling pathway)

FunctionalEvidence: Exogenous LRP5 expression in NIH3T3 cells increases the activity of the canonical Wnt signaling transcription factor LEF1 only when combined with exogenous expression of the Wnt-1 ligand in a separate population of cells grown in co-culture (Figure 1). This function is related to the phenotype in that canonical Wnt signaling is known to mediate bone formation.

FunctionalHPO: HP:0004349 (reduced bone mineral density), osteoporosis (HP:0000939), HP:0020110 (bone fracture)

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing of all 14 exons of RPE65

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

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

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

ClinVar: 98821, 13114

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

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

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

CasePMIDs: N/A

ExperimentName: CRISPR/Cas9-based rescue of patient variant in the mouse RPE

RescueModel: Mus musculus

GeneAlteration: The Kcnj13W53X/+ΔR model has been generated from Kcnj13W53X/+ mice by retinal pigment epithelium-specific introduction of the variant encoding the p.Trp53Ter nonsense variant.

RescueVariant: Rescue was performed by editing the variant to restore wild-type KCNJ13, not by introducing an additional human variant.

RescuePhenotype: The rescued phenotypes are full-field electroretinogram responses measured at week 10 post-injection and retinal thickness by optical coherence tomography.

RescueMethod: This rescue model has subretinally injected sgRNA to edit the W53X allele and restore the wild-type by CRISPR/Cas9 base editing.

RescueEvidence: The ERG c-wave from the RPE layer shows 55% higher amplitude for the edited/targeted retina relative to the non-targeted control (Figures 6J and 6K) and is accompanied by intact retinal structure by OCT (Figures 6H and 6I).

ModelVariant: NM_002242.4(KCNJ13):c.158G>A (p.Trp53Ter), ClinVarID: 224857

FamilyLabel: Liu_2007_Family

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

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

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

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

CountryOrigin: China

Ethnicity: Chinese

Race: Not specifically described

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

Family#Method1: Linkage mapping and haplotype analysis

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

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

Affected: 4 fully genotyped, 9 total

Unaffected: 7 fully genotyped

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

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

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Liu_2007_Family_Patient_V-10

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

ClinVar: 10522

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

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

FamilyAddInfo: The family is not reported to be consanguineous.

FamilyPMIDs: N/A

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

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: Sanger sequencing of all RPE65 exons

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

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

ClinVar: 13117 (homozygous)

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

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

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

CasePMIDs: N/A

PMID: 32666594

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

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

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

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

CaseNotHPOFreeText: Features of syndromic retinal dystrophy

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

CaseMethod1: Limited genetic testing for 13 candidate genes

CaseMethod2: N/A

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

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

CAID: CA411539826

gnomAD: The variant is not found in gnomAD.

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

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

CasePMIDs: N/A

PMID: 14962443

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

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

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

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

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

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

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

CaseMethod2: N/A

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

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

ClinVar: 98563

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

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

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: No deformity of long bones was observed.

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

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

CaseMethod2: N/A

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

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

ClinVar: 40288, 40290

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

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

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

CasePMIDs: N/A

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

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

CaseHPOFreeText: The proband has been previously diagnosed with achromatopsia.

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

CaseNotHPOFreeText: N/A

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

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

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

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

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

ClinVar ID: 487693, 487691

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

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

CaseAddInfo: N/A

CasePMIDs: N/A

ExperimentName: Homozygous disruption of the chicken ortholog of GUCY2D

NonHumanModel: Gallus gallus domesticus

GeneAlteration: The null allele of the chicken Rd gene (orthologous to human GUCY2D) exhibits a rearrangement in which a 723-bp region corresponding to exons 4-7 has been replaced by an in-frame insertion of 81-bp fragment likely derived from exon 9. This deletes the transmembrane domain and is predicted to result in complete inactivation of the enzyme. This variant has been studied in the homozygous state.

ModelPhenotype: HP:0007875 (Congenital blindness), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), Optokinetic reflex,

HumanPhenotype: HP:0007663 (Reduced visual acuity), HP:0007688 (Undetectable light- and dark-adapted electroretinogram), HP:0007703 (Abnormality of retinal pigmentation)

ModelEvidence: Chickens harboring the null variant in a homozygous state have dramatically lower levels of cGMP in the retina (Figure 1) and absent expression of GC1, the GUCY2D ortholog (Figure 2). Rod and cone photoreceptor cells develop normally, but have little to no function according to ERG. This is similar to the normal fundus appearance in LCA patients, despite severe early vision loss.

ModelVariant: The mouse model disrupts the expression of the endogenous GC1 protein product but does not feature knock-in of a variant from a human patient.

PMID: 31606330

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: 31607844

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: 11978759

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

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

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

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

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

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

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

ClinVar: 9357

gnomAD: The variant was not found in gnomAD.

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

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of PRPH2

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

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

ClinVar ID: 98707

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

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

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

CasePMIDs: N/A

Case#: Wang_2021_Patient_III-1, male, 32 years old, ethnicity described as Chinese

CasePresentingHPOs: HP:0000533 (Chorioretinal atrophy), HP:0007754 (Macular dystrophy), HP:0025158 (Hyperautofluorescent retinal lesion), HP:0001123 (Visual field defect), HP:0007994 (Peripheral visual field loss), HP:0030474 (Undetectable dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram), HP:0000662 (Nyctalopia), HP:0000529 (Progressive visual loss), HP:0000551 (Color vision defect), HP:0030534 (Abnormal best corrected visual acuity test), HP:0007737 (Bone spicule pigmentation of the retina),

CaseHPOFreeText: The proband has been diagnosed with cone-rod dystrophy, with the family exhibiting X-linked pattern of inheritance.

CaseNotHPOs: HP:0012632 (Abnormal intraocular pressure)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and was subjected to whole-exome sequencing.

CaseMethod1: Whole-exome sequencing

CaseMethod2: Sanger sequencing to confirm candidate variants within the RPGR locus

CaseGenotypingMethod: The proband and was subjected to whole-exome sequencing, followed by Sanger sequencing to confirm candidate variants within the RPGR locus and to genotype family members.

Variant: The proband harbors the NM_001034853.2(RPGR):c.2383G>T (p.Glu795Ter) variant in the hemizygous state.

ClinVar: 975145

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

VariantEvidence: NM_001034853.2(RPGR):c.2383G>T (p.Glu795Ter) is a nonsense variant in the final exon (exon 15) that is not predicted to trigger nonsense-mediated decay but truncates ~31% of the C-terminus of the protein product. In HEK-293T cells, truncation was confirmed by western blotting (Figure 3b), yet immunocytochemistry showed normal (cytoplasmic) localization (Figure 3c).

CaseAddInfo: The proband is a member of a family with three other affected males and three carrier females described as unaffected.

CasePMIDs: N/A

PMID: 1419803

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2B

MONDO: 0015629

InheritancePattern: Autosomal Dominant

Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral ((PMID: 28847738).

Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants