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

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

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

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

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

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

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

CAID: CA397953755

gnomAD: The variant was not found in gnomAD.

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

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

CasePMIDs: PMID: 23734073

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

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

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

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

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

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

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

ClinVar: 9357

gnomAD: The variant was not found in gnomAD.

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

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

CasePMIDs: N/A

PMID: 14609846

Gene: NYX

HGNC: 8082

Disease: Congenital stationary night blindness 1A

MONDO: 0010690

InheritancePattern: X-linked recessive

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

Penetrance: Penetrance is thought to be complete.

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: Normal OFF response

CasePreviousTesting: N/A

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

CaseMethod2: Haplotype analysis using microsatellite markers surrounding the NYX locus

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

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

CAID: CA412991558

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

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

CaseAddInfo: N/A

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: Normal OFF response

CasePreviousTesting: N/A

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

CaseMethod2: Haplotype analysis using microsatellite markers surrounding the NYX locus

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

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

CAID: CA2573050969

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

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

CaseAddInfo: N/A

CasePMIDs: N/A

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: linkage mapping

CaseMethod2: Sanger sequencing of BBS1

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

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

ClinVar ID: 12143

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

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

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

CasePMIDs: N/A

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

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

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

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

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

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

CAID: CA2573131867

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

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

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

CasePMIDs: N/A

PMID: 19390656

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

CasePresentingHPOs: HP:0006934 (Congenital nystagmus)

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

CaseNotHPOs: N/A

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

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

CaseMethod1: linkage analysis

CaseMethod2: Sanger sequencing

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

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

CAID: CA2573320693

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

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

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

CasePMIDs: N/A

PMID: 26114493

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).

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

PMID: 15914600

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: Lin_FamilyA_II:2

CasePresentingHPOsFreeText: Ophthalmic examination notes were retrospectively reviewed in patients. Best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, fundus examination, spectral-domain optical coherence tomography (SD-OCT) scans through the fovea, and short-wavelength fundus autofluorescence (SW-AF, 488 nm), were obtained in all four affected patients with Spectralis HRA+OCT (Heidelberg Engineering, Heidelberg, Germany). Full-field electroretinogram (ERG) testing was performed according to the International Society for Clinical Electrophysiology of Vision (ISCEV) standards. The patients in this study exhibited chorioretinal phenotypes characteristic of RP (Figure 1). All patients initially presented with night blindness followed by progressive constriction of their visual field. ERG recordings were collected from three patients (A-II:2, B-II:1, and D-II:5) (Figure 3). For A-II:2 at 60 years of age and D-II:5 at age 37 years of age, ERG rod responses of the right eyes were almost undetectable.

CasePreviousTesting: WES

CaseGenotypingMethod: Genetic testing was performed in all four patients in this study, using either whole exome sequencing (WES, A-II:2, B-II:1, and D-II:5)

Variant: c.226C>T (p.Arg76Ter)

ClinVarID: or CAID: CA151548

gnomAD: allele frequency of 0.001173 in the Latino population

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

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

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

CaseHPOFreeText: ERG with absent oscillatory-potential wavelets

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

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing of PCR amplified exons from NYX

CaseMethod2: N/A

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

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

ClinVar: 11423

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

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

CaseAddInfo: Phenotype information is found in PMID: 12397430.

CasePMIDs: 12397430

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

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

CaseHPOFreeText: ERG with absent oscillatory-potential wavelets

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

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing of PCR amplified exons from NYX

CaseMethod2: N/A

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

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

ClinVar: 99843

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

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

CaseAddInfo: Phenotype information is found in PMID: 12397430.

CasePMIDs: 12397430

ExperimentName: Murine model of PDE6A loss-of-function (Pde6Anmf363/nmf363)

NonHumanModel: Mus musculus

GeneAlteration: Mice were found to develop retinal degeneration due to a homozygous missense variant (2159G>A) at codon 670 substituting glycine for aspartic acid.

ModelPhenotype: HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0030478 (Abnormal amplitude of dark-adapted bright flash electroretinogram)

HumanPhenotype: HP:0011463 (Childhood onset), HP:0000662 (Nyctalopia), HP:0007994 (Peripheral visual field loss), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0007984 (Electronegative electroretinogram)

ModelEvidence: This mutation caused photoreceptor outer nuclear layer outer segment thinning (Figures 2C, 2D, 7), decreased dark-adapted bright flash ERG amplitude (Figure 2E), and decreased cGMP/PDE activity (Figure 3C).

ModelVariant: The model does not harbor a variant equivalent to one from the human patients, but rather has a mutagenesis-induced missense variant disrupting Pde6a leading to partial loss-of-function.

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.

ExperimentName: Targeted disruption of Lrp5 in mice

NonHumanModel: Mus musculus

GeneAlteration: Model animals were subjected to targeted disruption of Lrp5 by inserting an IRES-LacZ-Neomycin cassette to replace the region encoding the extracellar domain, starting at amino acid 373.

ModelPhenotype: HP:0004349 (Reduced bone mineral density), HP:0410280 (Pediatric onset), decreased osteoblast proliferation, HP:0007968 (Remnants of the hyaloid vascular system), failure of macrophage-mediated endothelial cell apoptosis

HumanPhenotype: HP:0000939 (Osteoporosis), HP:0011463 (Childhood onset), HP:0000541 (Retinal detachment), HP:0007968 (Remnants of the hyaloid vascular system), HP:0008046 (Abnormal retinal vascular morphology), HP:0000618 (Blindness), HP:0001249 (Intellectual disability), HP:0020110 (Bone fracture), HP:0000938 (Osteopenia), HP:0000926 (Platyspondyly)

ModelEvidence: Model animals subjected to targeted disruption of Lrp5 resembled human patients in that they exhibited reduced bone mineral density in the post-natal stage (Figs. S2, 3A), decreased osteoblast proliferation (Fig. 4), delayed ossification (Fig. 5), and remnants of the hyaloid vascular system due to failure of macrophage-mediated endothelial cell apoptosis (Fig. 8).

ModelVariant: The model features disruption of the wild-type Lrp5 gene, but not a mutation equivalent to a human variant.

PMID: 8111389

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).

PMID: 35138024

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

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 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.

Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).

Note: No variants found in PRPF4 in affected patients.

Case#: Case report, 11 year old, female, Korean

CaseHPOs: HP:0007663, HP:0000603, HP:0025010, HP:0000551 (reduced visual acuity, bilateral central scotoma, foveal atrophy, severe color vision deficiency)

CaseHPOsFreeText: Onset at 4 years old. BCVA in both eyes were 20/40, 20/50, and 20/100 at 4, 10, and 11 years, respectively. Cycloplegic refraction showed –0.5 D spherical error with astigmatism of –3.0 D cylindrical error in the right eye, and –1.0 D spherical error with astigmatism of –3.5 D cylindrical error in the left eye. The fundus examination showed slightly atrophic fovea (Figure 1A). Fundus autofluorescence showed hyperfluorescent fovea in both eyes, which may be an artifact (Figure 1A). SD-OCT showed an ellipsoid zone defect in both macular areas with an intact periphery (Figure 1A). Light-adapted 3 ERG and 30 Hz flicker ERG showed almost extinguished wave, while dark-adapted 0.01 ERG and 3 ERG also showed reduced amplitude (Figure 1B). Diagnosis – Cone Rod dystrophy

CasePreviousTesting: As part of this study - No pathogenic variants were identified in the other 97 genes associated with retinal degeneration, including 8 genes known to be associated with AR-CRD (ABCA4, ADAM9, C8orf37, CERKL, EYS, PROM1, RPGRIP1, and TULP1).

CaseMethod1: NGS

CaseGenotypingMethod: NGS of 98 genes known to be associated with inherited retinal degenerations (including cone-rod dystrophy), with confirmation of the identified variant by Sanger sequencing.

Variant: NM_004249.3:c.68C>T (p.Ser23Phe), homozygous

ClinVar: N/A

CAID: CA2860239

gnomAD: The highest population minor allele frequency in gnomAD v2.1.1 is 0.0004158 in the East Asian population; no homozygotes in any population.

VariantEvidence: 3D structures of the wild type and mutated RAB28 proteins, predicted using SWISS-MODEL, showed the p.Ser23Phe variant is located in the GTP binding region. Multiple in silico predictors, including SIFT, PolyPhen, CADD, suggest that the variant is damaging.

CaseAddInfo: Parents are not related. Parents and male sibling had normal vision and fundus findings and all were heterozygous for the RAB28 variant.

PMID: 28644393

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: 1356371

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

Selection B - Gene function is consistent with phenotype.

GOterm: GO:0007168 (receptor guanylyl cyclase signaling pathway)

FunctionalEvidence: Exogenous expression of the gene product in 293 cells exhibits a high level of cGMP production activity. When combined with the in situ hybridization evidence showing its expression along the retinal outer nuclear layer (coinciding with the rod and cone photoreceptor cell nuclei), this biochemical evidence indicates a function in synthesizing cGMP to promote recovery of the dark state following phototransduction.

FunctionalHPO: HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0007688 (Undetectable light- and dark-adapted electroretinogram), HP:0007703 (Abnormality of retinal pigmentation)

PhenotypeEvidence: The ability of the exogenously expressed enzyme to efficiently catalyze cGMP production (Figure) is consistent with the loss of photoreceptor function that is characteristic of the disease, as abnormalities in cGMP levels have long been associated with photoreceptor degeneration (PMID: 4369896).

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

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: as mentioned

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

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

ClinVar: 56528 and 128778 (in cis, homozygous)

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

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

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

CasePMIDs: N/A

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

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

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

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

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

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

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

CaseMethod2: as mentioned

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

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

ClinVar: 56539 (homozygous)

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

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

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: as mentioned

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

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

CAID: CA611398060 (homozygous)

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

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

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

CasePMIDs: N/A

PMID: 24959063

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

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 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.

Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).

PMID: 27032803

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: next-generation sequencing panel

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

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

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

ClinVar ID: 12143, 802688

gnomAD: The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1 The NM_024649.5(BBS1):c.118del (p.Cys40fs) variant is found in gnomAD v2.1.1 at a frequency of 0.00005782 (2 alleles / 34592 total alleles, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/11-66278553-CT-C?dataset=gnomad_r2_1

VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant. NM_024649.5(BBS1):c.118del (p.Cys40fs) is a frameshift variant in exon 2 of 17 that is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 93% of the protein product.

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

CasePMIDs: N/A

PMID: 25766589

Gene: RBP3

HGNC: 9921

Disease: retinitis pigmentosa 66

MONDO: 0014093

InheritancePattern: autosomal recessive

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

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

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

ExperimentName: RPE65 expression is highly specific to the retinal pigment epithelium

TissueExpression: pigmented layer of retina (also known as retinal pigment epithelium, UBERON:0001782)

ExpressionEvidence: RPE65 protein was first detected using an RPE-specific monocolonal antibody raised against human retinal pigment epithelium (RPE) cells. Retina-specific gene expression data from a separate publication (PMID: 30239781, https://eyeintegration.nei.nih.gov/) confirm that RPE65 expression is highly specific to the retina relative to other tissues within the eye or the human body in general. Note where the evidence is found in the article.

PMID: 30640974

Gene: CTNNB1

HGNC: 2514

Disease: severe intellectual disability-progressive spastic diplegia syndrome

MONDO: 0014035

InheritancePattern: autosomal dominant

Prevalence: The incidence is unknown but estimated to be between 1 in 30,000 and 1 in 40,000 births (PMID: 32168371).

Penetrance: The penetrance of the cognitive impairment phenotype among cases appears to be near-complete, while the exudative vitreoretinopathy phenotype reportedly has a prevalence of ~39% among affected individuals with a syndromic diagnosis.

ExperimentName: GPR143 over-expression in neuroendocrine tumor cells

NonPatientCell: CL:0000336 (adrenal medulla chromaffin cell, specifically the PC-12 cell line)

GeneFunction: GO:0031175 (neuron projection development)

GeneAlteration: Over-expression of GPR143 was accomplished by stable transfection of PC-12 cells with mCherry-tagged wild-type or mutant GPR143.

FunctionalEvidence: Figure 4C indicates that GPR143 over-expression decreases the # of neurites longer than 100 microns, and that this occurs through a mechanism that is dependent on the G-protein Galpha13. Figure 5E shows that this effect of wild-type GPR143 is particularly pronounced for neurites longer than 150 microns, and is not mimicked by GPR143 missense variants reported in patients.

FAVariants: Patient-associated variants were p.Asp78Asn (ClinVar: 98620), p.Trp133Arg (ClinVar: 10516 or 10519), p.Ile261Asn (CAID: CA411996177), and p.Trp292Gly (ClinVar: 98647).

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.

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: next-generation sequencing panel (44 genes)

CaseMethod2: Sanger sequencing of PRPH2

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

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

ClinVar ID: 13179

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

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

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

CasePMIDs: N/A

PMID: 26061163

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).

GroupName: Tabata_1998_Group

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

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupDemographics

NumberMales: 4

NumberFemales: 5

CountryOrigin: Japan

Ethnicity: Not mentioned

Race: Not mentioned

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

TotalNumber: 9

FamilyInfo: 9

NoFamily: 0

VariantCount: 5

NonVariant: 4

OtherVariant: N/A

GroupPreviousTesting: Sanger sequencing of PCR-amplified exon 5

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

FamilyLabel: Tabata_1998_Family_Ch

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

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

FamilyNotHPOs: HP:0007994 (Peripheral visual field loss)

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

CountryOrigin: Japan

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

Family#GenotypingMethod: Sanger sequencing

Affected: 2

Unaffected: 3

Segregations: N/A

PublishedLOD: N/A

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Tabata_1998_Family_Ch_patient_1

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

CAID: CA1139771334

gnomAD: Variant is absent from gnomAD.

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

FamilyPMIDs: N/A

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

DiseaseAssertion: Sorsby's fundus dystrophy

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

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

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

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

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

CasePreviousTesting: PCR-based heteroduplex analysis using gel electophoresis

CaseGenotypingMethod: Sanger sequencing

PreviouslyPublished: N/A

SupplementalData: N/A

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

CAID: CA1139771334

gnomAD: Variant is absent from gnomAD.

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

PMID: 17574030

Gene: BBS7

HGNC: 18758

Disease: Bardet-Biedl syndrome 7

MONDO: 0014435

InheritancePattern: autosomal recessive

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

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

ExperimentName: 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.

PMID: 34800980

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#: 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: 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

Case#: proband, F, Age of Report: 11 y.o., Ethnicity: European ancestry.

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa), HP:0000662 (Nyctalopia), HP:0007737 (Bone spicule pigmentation of the retina), HP:0001250 (Seizure)

CaseHPOFreeText: The proband of European ancestry was referred at the age of 11 yr for a recent diagnosis of retinitis pigmentosa (II:3). She reported a several-year history of nyctalopia. At her initial visit, her VA was 20/20 in both eyes [oculus uterque (OU)]. GVF testing was unreliable at this visit, and results are not shown. ERG testing showed barely recordable responses in both eyes. Fundus examination showed early optic nerve pallor and surface gliosis, vascular attenuation, depressed foveal reflex, and fine retinal pigment epithelium (RPE) granularity. Peripheral retina showed a few areas of bone spicule-like pigmentation and a coarse RPE granularity. When re-evaluated at the age of 17 yr, her vision was reduced to 20/30 OU and visual fields were constricted (Fig. 1D, i and ii). Testing at the age of 24 yr demonstrated further reduction of VA to 20/50 right eye [oculus dexter (OD)] and 20/30 left eye [oculus sinister (OS)] with greatly constricted visual field (Fig. 1D, iii and iv). Fundus examination showed heavy bone spicule pigmentation in the equatorial region OU (Fig. 1C). Medical history was significant for a history of petit mal seizures beginning at the age of 8 yr, which were controlled with medication.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WGS.

Variant: Variant 1: NM_021831.6:c.841C>T (p.Arg281Cys). Variant 2: NM_021831.6:c.1459C>T (p.Arg487Ter).

ClinVar: Variant 1: 1036269. Variant 2: N/A.

CAID: Variant 1: CA1567739. Variant 2: CA1567876.

gnomAD: Variant 1: Frequency: 0. Link: https://gnomad.broadinstitute.org/variant/chr2-27055186-C-T?dataset=gnomad_r4. Variant 2: Frequency: 0.000003590. Link: https://gnomad.broadinstitute.org/variant/chr2-27056716-C-T?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: The proband's brother (II:2) was initially evaluated at the age of 15 yr. He also reported a history of impaired night vision. His visual acuities were 20/15 OD and 20/20 OS. GVF testing showed full fields with the V4e isopter, but constriction to 30 degrees centrally with the I4e isopter. The scotopic ERG was barely recordable and photopic responses showed 50% reduction of amplitude and normal waveform. Fundus examination showed slight optic disc pallor and gliosis. Vessels were attenuated. The foveal reflex was intact in both eye, and the RPE was intact in both maculae. The peripheral retina showed fine bone spicule pigmentation and fine granularity to the RPE. Aside from the history of seizures as a child in the proband, these patients reported no other ocular or nonocular abnormalities and had a diagnosis of recessive retinitis pigmentosa.

CasePMIDs: N/A.

Case#: Patient F1-IV:3, M, Age of Report: 32 y.o., Ethnicity: N/A.

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa), HP:0011505 (Cystoid macular edema/cystoid maculopathy), HP:0007663 (Reduced visual acuity), HP:0500081 (Pseudophakia),

CaseHPOFreeText: Patient F1-IV:3 was referred to the Rotterdam Eye Hospital at age 32 with end-stage RP complicated by cystoid maculopathy. Visual acuity at presentation was hand movements in the right and light perception in the left eye. He was pseudophakic (cataract extraction performed at age 29), and retrospective data on visual acuity and visual fields were not available. The cystoid maculopathy was responsive to subcutaneous octreotide, but visual acuity did not improve. Through the years the cysts disappeared and atrophy of the macular region developed (Figs. 2A, 2B). He was also suffering from Behcet's disease, but did not have a history of recurring uveitis.

Stratus OCT of the right eye in F1-IV:3 (B) at age 34 showed large cysts at the macula comprising several retinal layers with cysts in the inner nuclear layer of the paramacular region (upper). In the lower scan (at 39 years), complete atrophy of retinal layers at the fovea can be observed.

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

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

All patients developed posterior subcapsular cataract.

CaseNotHPOs: N/A.

CaseNotHPOFreeText:N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_021831.6:c.1775G>A (p.Trp592Ter).

ClinVar: N/A.

CAID: CA1567964.

gnomAD: Frequency: 2.800e-7. Link: https://gnomad.broadinstitute.org/variant/chr2-27058503-G-A?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: His older sister (F1-IV:2) was examined only once, at the age of 43. She also presented with end-stage RP. She was pseudophakic, and visual acuity was hand movement and counting fingers. Her fundus examination revealed optic disc pallor, attenuated vessels, macular atrophy, midperipheral and peripheral RPE atrophy, and heavy bone spicule pigmentation but no cystoid macular edema (not shown). The DNA sample of this patient was not available.

CasePMIDs: N/A.

Case#: F3-II.1, F, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007994 (Peripheral visual field loss), HP:0032037 (Mildly reduced visual acuity),

CaseHPOFreeText: Very limited photoreceptor preservation for F3-II.1

Patients from families 2 and 3 initially developed nyctalopia, with a range of onset from 9 to 30 years before subsequent development of peripheral visual field loss. At last review (age range, 24–45 years), there was mild visual acuity loss with best-corrected visual acuity mean 0.34 logMAR (range, 0.30–0.48). There were fundus abnormalities consistent with RP including attenuated vessels, macular and midperipheral RPE mottling/atrophy, and peripheral intraretinal pigment migration, most prominent in the proband of family 3 (Fig. 2I). A partial ring of reduced autofluorescence in F3-II:1 (Figs. 2D, 2G, 2J).

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

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

All patients developed posterior subcapsular cataract.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WGS.

Variant: Variant 1: NM_021831.6:c.752T>G (p.Val251Gly). Variant 2: NM_021831.6:c.1504dup (p.Ala502GlyfsTer15).

ClinVar: Variant 1: N/A. Variant 2: N/A.

CAID: Variant 1: CA346174950. Variant 2: CA2586968850.

gnomAD: Variant 1: Frequency: 2.800e-7. Link: https://gnomad.broadinstitute.org/variant/chr2-27053509-C-G?dataset=gnomad_r4. Variant 2: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

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.

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.

PMID: 9843205

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

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

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

PMID: 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

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

ExperimentName: High GUCY2D mRNA expression in human retina relative to other tissue types

TissueExpression: Retina (UBERON:0000966)

ExpressionEvidence: Evidence can be accessed on the publication-associated website (https://eyeintegration.nei.nih.gov/) through the Pan-Tissue Plots feature.

FamilyInfo: Family A, German, Pedigree in Fig 1

FamilyHPOs: HP:0007663, HP:0011003, HP:0008001, HP:0030602, HP:0000551, HP:0000603, HP:0000512 (reduced visual acuity, high myopia, foveal hyperpigmentation, hyperfluorescent fovea, color vision defect, central scotoma, abnormal ERG)

FamilyHPOFreeText: All 3 affected family members were diagnosed with CRD in the second decade of life. Optical coherence tomography (OCT) displayed altered photoreceptors in the fovea, whereas the peripheral photoreceptors are intact (Figure 2C, and 2A, 2B). On ERG photopic responses were nondetectable and scotopic responses reduced in all three siblings.

FamilyMethod1: Homozygosity mapping

FamilyMethod2: WES

FamilyGenotypingMethod: Homozygosity mapping, using Affymetrix GeneChip Human Mapping 250K SNP arrays, in 3 affected siblings revealed a shared homozygous region of 4.68 Mb on chromosome 4 containing 15 genes. Subsequently, exome sequencing was performed in 2 of the affected sibling, A-II:1 and A-II:2. No pathogenic variants in the genes known to be mutated in arCRD (ABCA4, ADAM9, C8orf37, CERKL, EYS, RPGRIP1, and TULP1) were observed among the shared variants. RAB28 variant confirmed by Sanger sequencing.

Variant: NM_001017979.2:c.565C>T (p.Glu189Ter), homozygous, (all 3 affected individuals are homozygous, parents not tested)

ClinVar: 60754

gnomAD: Not in gnomAD.

Proband: A-II:1, 14 years at diagnosis, 28 years at last visit, German

CaseHPOsFreeText: Refractive error OD -16D SE, OS -15.5D SE; visual acuity OD 20/320 OS 20/200; hyperpigmented foveal region; autofluorescence showed hyperfluorescent area at foveal region; OCT showed irregular inner and outer segments in fovea, thinning of other retinal layers of fovea; color vision using D-15 Panel showed tritan and defects in scotopic lines; visual field showed concentric reduction to 15–20 degrees (III/4); ERG at age 16 revealed nondetectable cone function and reduced rod responses.

FamilyLabel: Morimura_1998_Family_7828

FamilyPresentingHPOs: HP:0000546 (Retinal degeneration)

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

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: The Dominican Republic

Ethnicity: Not mentioned

Race: Not mentioned

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

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

Affected: 5

Unaffected: 5

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

PublishedLOD: N/A

eLOD: 3.03

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

ProbandLabel: Morimura_1998_Patient_III-4

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

ClinVar: 13118, 98831

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

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

FamilyPMIDs: N/A

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

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

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

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

ClinVar: 13115 (homozygous)

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

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

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

CasePMIDs: N/A

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.

PMID: 21051334

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

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 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.

Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).

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

PMID: 8634705

Gene: GPR143

HGNC: 20145

Disease: X-linked recessive ocular albinism

MONDO: 0021019

InheritancePattern: X-linked recessive

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

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

Case#: 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

PMID: 18976725

Gene: EYS

HGNC: 21555

Disease: Retinitis pigmentosa 25

MONDO: MONDO:0011272

InheritancePattern: autosomal recessive

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

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

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#: JU1426 (Family 10, II:3), Japanese male, 59 years (report)

CaseHPOsFreeText: Best-corrected visual acuity of zero in both eyes; fundus exam - inconspicuous, partial white dots at peripheral retina, and macular degeneration in both eyes; reduced fundus autofluorescence, and irregular autofluorescence around fovea in both eyes; Optical coherence tomography - diffuse disruption of ellipsoid zone and interdigitation zone with foveal sparing in both eyes; 30 min dark adapted ERG showed extinguished b-waves, and with dark adaptation of 2-3 hours there was partial recovery of b-waves.

CaseGenotypingMethod: WES

Variant: NM_002905.4:c.259C>T (p.Gln87Ter) homozygous

ClinVar: N/A

CAID: CA385200238

gnomAD: Not in gnomAD

CaseAddInfo: Estimated age (based on years of follow up)

Score: 2 points. This individual, with a diagnosis of fundus albipunctatus is homozygous for a nonsense variant in RDH5. This variant is absent in gnomAD.

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

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

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

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

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

CaseNotHPOFreeText: N/A

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

CaseMethod1: targeted exome or whole exome sequencing

CaseMethod2: Sanger sequencing of OPN1LW

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

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

CAID: CA3071606830

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

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

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

CasePMIDs: N/A

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

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

DiseaseAssertion: Sorsby fundus dystrophy

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

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

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

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Phenotypic characterization only

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

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

SupplementalData: N/A

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

CAID: CA411540365

gnomAD: Variant is absent from gnomAD.

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

PMID: 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.

PMID: 36140676

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#: 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.