Case#: Patient 1, F, Age of Report: 32 y.o. Age of Onset: 28 y.o, Ethnicity: N/A.

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0007737 (Bone spicule pigmentation of the retina), HP:0030648 (Midperipheral), HP:0000543 (Optic disc pallor/waxy pallor of the optic disc), HP:0001133 (Constriction of peripheral visual field/constricted field with a remaining small central island)

CaseHPOFreeText: 32-year-old female presented four years ago with a unilateral decrease in vision in the left eye that she had had for a number of years. There was no family history of blindness or inherited eye diseases and her parents were first cousins.

She denied a previous history of ocular trauma, surgery and ocular inflammation. Her medical and drug history were unremarkable. The patient denied any neurological or hearing problems. She had best-corrected visual acuity (BCVA) of 20/20 and 20/40 in the right and left eye, respectively. Anterior segment examination of both eyes, as well as fundus examination of the right eye were unremarkable. Fundus examination of the left eye revealed midperipheral bone spicules, attenuated blood vessels and a waxy pallor of the optic disc (Figure 1).

Fundus autofluorescence revealed hypoautofluorescence corresponding to the bone spicules and hyperautofluorescence at the macular area with preserved foveal autofluorescence. SD-OCT of the right eye was unremarkable, while the left eye showed the loss of the parafoveal ellipsoid zone. The subfoveal ellipsoid zone was minimally affected. ffERG showed responses within normal limits in the right eye and non-recordable responses in the left eye (Figure 2). The Goldman visual field was normal in the right eye, while the left revealed a severely constricted field with a remaining small central island.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: NGS.

Variant: Variant 1: NM_021831.6:c.373C>T (p.Arg125Trp). Variant 2: NM_021831.6:c.730-22_730-19dup (n.730-22_730-19dup).

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

CAID: Variant 1: CA1567613. Variant 2: CA2586968849.

gnomAD: Variant 1: Frequency: 0.000007390. Link: https://gnomad.broadinstitute.org/variant/chr2-27053559-C-T?dataset=gnomad_r4. Variant 2: N/A.

VariantEvidence: N/A.

CaseAddInfo: Segregation analysis for parents and other family members was not possible. The patient had stable vision upon examination in both eyes during five years of follow-up visits with a stable average central macular thickness on SD-OCT (Table 2).

CasePMIDs: N/A.

Case: Patient 3

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

CasePreviousTesting:

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

Variant: c.208C>T (p.Arg70Trp)

ClinVarID: or CAID: CA412927449

gnomAD: not present in gnomAD v2.1.1

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

Case: Patient 2

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

CasePreviousTesting:

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

Variant: c.952_954del (p.Phe318del)

ClinVarID: or CAID: CA645509415

gnomAD: variant not present in gnomAD v2.1.1

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

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

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: targeted exome sequencing

CaseMethod2: Sanger sequencing of BBS1

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

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

ClinVar ID: 12143, 981241

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

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

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

CasePMIDs: N/A

Case#: Haider_2000_Proband_2, sex, age, and origin not reported

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

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

Variant: The individual harbors the NM_014249.4(NR2E3):c.200_208del (p.Cys67_Gly69del) variant in the homozygous state.

ClinVarID: 5531

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

VariantEvidence: NM_014249.4(NR2E3):c.200_208del (p.Cys67_Gly69del) is a short in-frame deletion variant within the zinc finger / DNA-binding domain of NR2E3.

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

CasePMIDs: N/A

Case#: Haider_2000_Proband_4, sex, age, and origin not reported

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

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

Variant: The individual harbors the NM_014249.4(NR2E3):c.227G>A (p.Arg76Gln) variant in the homozygous state.

ClinVarID: 5530

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.0004046 in the South Asian population (36 alleles / 88,984 total alleles, with 1 homozygote) https://gnomad.broadinstitute.org/variant/chr15-71811591-G-A?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.227G>A (p.Arg76Gln) is a missense variant within the zinc finger / DNA-binding domain of NR2E3, and occurs at the same amino acid position as another missense substitution reported in the same article.

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

CasePMIDs: N/A

Case: Lin_FamilyC_II:1

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: Genetic testing was performed in all four patients in this study, using either or targeted capture sequencing of 280 retinal dystrophy-related genes (C-II:1).

CaseGenotypingMethod: Genetic testing was performed in all four patients in this study, using either or targeted capture sequencing of 280 retinal dystrophy-related genes (C-II:1).

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

ClinVarID: or CAID: CA151548

gnomAD: allele frequency of 0.001173 in the Latino population

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

FamilyLabel: van_Huet_2014_Family_A, national origin reported as Dutch

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

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

Family#PresentingNotHPOs: N/A

CountryOrigin: Netherlands

Ethnicity: Reported as Dutch

Race: Not mentioned

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

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

Family#Method2: N/A

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

Affected: 3

Unaffected: 3

Segregations: Two segregations are reported in the family, with none inconsistent. The family is apparently not consanguineous. The pedigree is shown in Figure 1.

PublishedLOD: N/A

eLOD: 1.50

AddSegregationInfo: N/A

ProbandLabel: van_Huet_2014_Patient_A-II:1

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

ClinVar: 3547

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

FamilyAddInfo: Despite the homozygous state of the variant, the family is reportedly not consanguineous.

FamilyPMIDs: N/A

Case#: van_Huet_2014_Patient_F-II:2, female, age 10 years at time of onset, age 32 at the time of report, national origin reported as from Pakistan

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0011504 (Bull's eye maculopathy), HP:0100014 (Epiretinal membrane), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0000546 (Retinal degeneration), HP:0007737 (Bone spicule pigmentation of the retina)

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

CaseNotHPOs: HP:0000517 (Abnormal lens morphology, such as cataract)

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

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

ClinVar: 437938

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

VariantEvidence: The NM_016247.4(IMPG2):c.1680T>A (p.Tyr560Ter) variant is a nonsense variant in exon 13 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 55% of the protein product.

CaseAddInfo: The family is reportedly consanguineous, with the parents being first cousins. The proband has an affected brother and an affected mother who have the same genotype, as well as a heterozygous carrier father.

CasePMIDs: PMID: 20673862

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of autozygosity mapping (PMID: 20673862).

CaseMethod1: Homozygosity mapping

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

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

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

ClinVar: 191181, 3548

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

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

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

CasePMIDs: PMID: 20673862

PMID: 18836446

Gene: EYS

HGNC: 21555

Disease: Retinitis pigmentosa 25

MONDO: MONDO:0011272

InheritancePattern: autosomal recessive

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

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

PMID: 40172514

Gene: RP1L1

HGNC: 15946

Disease: occult macular dystrophy

MONDO: 0013316

InheritancePattern: autosomal dominant

Prevalence: The prevalence of occult macular dystrophy is "significantly less than one in 10,000 or 100,000 (https://www.reviewofoptometry.com/article/the-best-is-yet-to-come-feb).

Penetrance: The disease is known to be incompletely penetrant in family members carrying the heterozygous p.Arg45Trp variant (PMID: 20826268).

PMID: 23023527

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

PMID: 31736247

Gene: TOPORS

PMID: 32715858

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

FamilyLabel: DeBenedictis_2020_Family_1

Family#PresentingHPOs: HP:0000662 (Nyctalopia), HP:0000518 (Cataract), HP:0000964 (Eczema), HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0007703 (Abnormality of retinal pigmentation), HP:0007894 (Hypopigmentation of the fundus)

Family#PresentingHPOFreeText: Onset in 5th decade of life, initial diagnosis not with SFD but with retinitis pigmentosa.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: Features of syndromic retinal dystrophy

CountryOrigin: N/A

Ethnicity: Proband has Dutch ancestry on maternal (affected) side and North Irish / English on paternal (unaffected) side.

Race: Caucasian

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

Family#Method1: Limited genetic testing for 13 candidate genes

Family#Method2: N/A

Family#GenotypingMethod: next-generation sequencing analysis of an 856-gene retinal dystrophy panel

Affected: 2

Unaffected: 0

Segregations: There was 1 segregation reported, while consanguinity was not mentioned. The pedigree was not depicted.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: DiBenedetto_Patient_1

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

CAID: CA411539826

gnomAD: The variant is not found in gnomAD.

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

FamilyPMIDs: N/A

PMID: 35096838

Gene: KCNJ13

HGNC: 6259

Disease: Leber congenital amaurosis 16

MONDO: 0013613

InheritancePattern: autosomal recessive

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

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

PMID: 19657028

Gene: RP1L1

HGNC: 15946

Disease: occult macular dystrophy

MONDO: 0013316

InheritancePattern: autosomal dominant

Prevalence: The prevalence of occult macular dystrophy is "significantly less than one in 10,000 or 100,000 (https://www.reviewofoptometry.com/article/the-best-is-yet-to-come-feb).

Penetrance: The disease is known to be incompletely penetrant in family members carrying the heterozygous p.Arg45Trp variant (PMID: 20826268).

Case#: Huang_1995_Family_#3397_Patient_AR76, male, age and ethnic origin note mentioned

CasePresentingHPOs: 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)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Sanger sequencing of PDE6A has been performed in the patient and her affected family members.

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of PDE6A

CaseGenotypingMethod: The patient and his affected sibling were subjected to SSCP of PDE6A PCR products followed by Sanger sequencing to identify the variant.

Variant: The proband harbors the NM_000440.3(PDE6A):c.1032C>A (p.Ser344Arg) and NM_000440.3(PDE6A):c.1683G>A (p.Trp561Ter) variants in the compound heterozygous state.

ClinVar: 13111, 13112

gnomAD: NM_000440.3(PDE6A):c.1032C>A (p.Ser344Arg) was not found in gnomAD v2.1.1, while NM_000440.3(PDE6A):c.1683G>A (p.Trp561Ter) was found at a frequency of 0.000008792 (1/113736) in the European non-Finnish population. https://gnomad.broadinstitute.org/variant/5-149274791-C-T

VariantEvidence: NM_000440.3(PDE6A):c.1032C>A (p.Ser344Arg) is a missense variant in exon 7 of 22 total, and does not have evidence of a functional effect on the protein product. NM_000440.3(PDE6A):c.1683G>A (p.Trp561Ter) is a nonsense variant in exon 13 of 22 total, and is predicted to trigger NMD or to at least disrupt the C-terminal 35% of the protein product.

CaseAddInfo: The proband is from a family with an affected sibling and unaffected parents.

CasePMIDs: N/A

Case#: Huang_1995_Family_#3526_Patient_AR23, female, age and ethnic origin note mentioned

CasePresentingHPOs: 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)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Sanger sequencing of PDE6A has been performed in the patient and her affected family members.

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of PDE6A

CaseGenotypingMethod: The patient and her affected family members were subjected to SSCP of PDE6A PCR products followed by Sanger sequencing to identify the variant.

Variant: The proband harbors the NM_000440.3(PDE6A):c.1749C>G (p.Tyr583Ter) variant in the homozygous state.

ClinVar: 13110

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

VariantEvidence: NM_000440.3(PDE6A):c.1749C>G (p.Tyr583Ter) is a nonsense variant in exon 14 of 22 total, and is predicted to trigger NMD or to at least truncate ~32% of the protein product.

CaseAddInfo: The proband is from a family with two affected siblings, two unaffected siblings, and unaffected parents.

CasePMIDs: N/A

FamilyLabel: Bowne_2011_Family_TCD-G

Family#PresentingHPOs: HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0007994 (Peripheral visual field loss), HP:0000533 (Chorioretinal atrophy), HP:0000546 (Retinal degeneration)

Family#PresentingHPOFreeText: Onset was in the 2nd to 5th decade of life, typically with impaired dark adaptation. Genotype-positive members of the family exhibited a wide range of phenotypes.

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

CountryOrigin: Ireland

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: SNP-based linkage analysis was performed on all family members, mapping the phenotype of autosomal dominant retinitis pigmentosa to an 8.8-Mb genomic region located at chr1 p31. Whole exome sequencing of 3 affected an 1 unaffected family members then identified candidate variants of interest.

Family#Method1: SNP-based linkage analysis and whole exome sequencing of a subset of family members

Family#Method2: Candidate gene sequencing

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

Affected: 20

Unaffected: N/A

Segregations: 21 segregations were reported. 4 genotype-positive individuals were unaffected (reflecting reduced penetrance), with one of them having an affected child. The pedigree can be found in Figure 1a. Consanguinity of the family was not mentioned.

PublishedLOD: 3.6

eLOD: 6.32

AddSegregationInfo: 4 genotype-positive individuals were unaffected, with one of them having an affected child. Another non-genotyped but unaffected individual had an affected child as well. In combination with the 20 genotype-positive and phenotype-positive individuals, this reflects incomplete penetrance of approximately 80%.

ProbandLabel: Bowne_2011_Family_TCD-G_Patient_53

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

ClinVar: 750796

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

FamilyAddInfo: N/A

FamilyPMIDs: PMID: 20861475

Case#: Zeitz_2006_Family_A_II-5, male, onset in early childhood, family ancestry reported as Swiss

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

CaseHPOFreeText: The proband and his sibling have diagnosis of congenital stationary night blindness, in the absence of family history of the disease. BCVA was 20/100 at age 15 years. Disease course was stationary for 30 years but later included a decrease in visual acuity and development of moderate photophobia.

CaseNotHPOs: HP:0000662 (Nyctalopia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of PCR products from the CACNA1F gene. The authors also implied that similarly screening was performed all other known genes associated CSNB, which at the time included RHO, GNAT1, PDE6B, GRK1, SAG, NYX, and GRM6.

CaseMethod1: Sanger sequencing of CABP4

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was limited to Sanger sequencing of PCR products from the CACNA1F and CABP4 genes, with possible sequencing of other known CSNB-associated genes RHO, GNAT1, PDE6B, GRK1, SAG, NYX, and GRM6.

Variant: The individual harbors the NM_145200.3(CABP4):c.800_801delAG variant in the homozygous state.

ClinVar ID: 1952

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.00007043 in the European (non-Finnish) population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/11-67226099-CAG-C?dataset=gnomad_r2_1

VariantEvidence: NM_145200.3(CABP4):c.800_801delAG is a frameshift variant within exon 6 of 6 that is predicted not to trigger nonsense-mediated decay but rather to disrupt the C-terminal 9 amino acids (3%) of the protein product and to extend the remaining protein by 91 additional amino acids. Analysis of patient mRNA indicates that splicing occurs normally but that expression at the mRNA level is decreased by more than 50% relative to the unaffected family member control.

CaseAddInfo: The proband's family is reportedly non-consanguineous, and includes a similarly affected brother who is also homozygous for the variant, as well as unaffected parents and 4 unaffected siblings who are heterozygous or lacking the variant (Figure 2A). Family history was negative for CSNB.

CasePMIDs: N/A

FamilyLabel: Jacobson_1995_Family_1

Family#PresentingHPOs: HP:0000662 (Nyctalopia), HP:0011510 (Drusen), HP:0200056 (Macular scar), HP:0000608 (Macular degeneration), HP:0000603 (Central scotoma), HP:0025243 (Subretinal hemorrhage)

FamilyHPOFreeText: Onset in the 4th or early 5th decade of life with drusen appearing first and progression to macular scarring and degeneration.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: United States (mentioned in PMID:8981947)

Family#PreviousTesting: SSCP using PCR-amplified exon 5 from TIMP3, followed by Sanger sequencing of the exon 5 PCR product.

Family#GenotypingMethod: PCR amplification of exon 5 in samples from each family member, followed by enzyme digestion with the Bbv1 restriction endonuclease.

Affected: 6

Unaffected: 2

Segregations: 5

PublishedLOD: N/A

eLOD: 1.5

AddSegregationInfo: N/A

ProbandLabel: Jacobson_1995_Family_1_Patient_III-5

Variant: Patients harbor the NM_000362.5(TIMP3):c.568G>T (p.Gly190Cys) missense variant.

CAID: CA411540415

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

PMID: 27124789

Gene: PDE6C

HGNC: 8787

Disease: cone dystrophy 4

MONDO: 0013129

InheritancePattern: recessive

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

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

PMID: 18179881

Gene: BEST1

Case#: 46-year-old, M, Age of report: 46 y.o., Ethnicity: Han Chinese.

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa), HP:0001696 (Situs inversus totalis), HP:0003251 (Male infertility), HP:0000662 (Nyctalopia/Night blindness), HP:0012207 (Reduced Sperm Motility), HP:0011109 (Chronic sinusitis), HP:0000458 (Anosmia/Permanently impaired olfactory sensation), HP:0007688 (Undetectable light- and dark-adapted electroretinogram)

CaseHPOFreeText: Proband has consanguineous family.

The proband complained of pronounced vision decline over the last 2 years. He had experienced night blindness over the last decade and was diagnosed with RP at age 33. His best-corrected visual acuity (BCVA) was 0.6 in both eyes, with −3.75-0.75 × 85 OD and − 3.25-1.25 × 65 OS.

Dilated fundus examination revealed sparse bone spicule pigment deposits, widespread mottled pigmentation in the mid-peripheral retina, and attenuated retinal vessels (Figure 1A). Fundus autofluorescence imaging exhibited hypofluorescence outside the vascular arcades and a characteristic hyperfluorescent ring around the fovea (Figure 1B). Optical coherence tomography (OCT) images showed a retained central island within the outer nuclear layer and ellipsoid zone (Figure 1C). Electroretinography indicated extinguished responses.

Four-year follow-up data combined with past medical history revealed slow vision degeneration. BCVA in both eyes was 0.1 at age 41, 0.8 at age 44, and 0.5 at age 50. Fundoscopy demonstrated larger, more peripheral retinal pigment epithelium atrophy with age, corresponding to hypofluorescent patches in fundus autofluorescence (Figure 1B). OCT images demonstrated ellipsoid zone peripheral loss, which progressed to the central fovea over time (Figure 1C). The severe peripheral visual field constriction observed in his forties worsened considerably with age. At age 50, all peripheral visual fields outside the central 5° were bilaterally lost (Figure 1D).

A review of his medical history during the second visit revealed full thoracic and abdominal situs inversus (Figure 1E). Routine semen analysis found that sperm motility was severely reduced, resulting in infertility (Table 1). Furthermore, this patient had chronic sinusitis, and olfactory sensation was permanently impaired following a severe cold at age of 49.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: Next-generation sequencing. Sanger sequencing and segregation analysis indicated his siblings carried the same heterozygous variant (Figure 2A, B).

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Whole exome sequencing (WES) for proband and his siblings

Variant: NM_012106.4:c.22_23del.

ClinVar: N/A.

CAID: CA495624174.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: Gong_2001_Proband_5, no reported gender, age or national origin

CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

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

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

Variant: The patient harbors the NM_002335.4(LRP5):c.2557C>T (p.Gln853Ter) variant in the homozygous state.

ClinVar: 6272

gnomAD: The NM_002335.4(LRP5):c.2557C>T (p.Gln853Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.2557C>T (p.Gln853Ter) is a nonsense variant in exon 12 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~47% of the protein product. It appears to be stable at the protein level but is not secreted in the exogenous expression system, consistent with loss-of-function rather than dominant negative effect.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

Case#: Ebenezer_2005_Family_A_Patient_III.4, male, age not specified, family origin reported to be British

CasePresentingHPOs: HP:0025710 (Late young adult onset), HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0000613 (Photophobia), HP:0007803 (Monochromacy), HP:0031624 (Moderate myopia), HP:0001103 (Abnormal macular morphology), HP:0000533 (Chorioretinal atrophy), HP:0500087 (Peripapillary atrophy), HP:0025159 (Hypoautofluorescent retinal lesion), HP:0030844 (Undetectable pattern electroretinogram), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, with the family exhibiting an X-linked pattern of inheritance. Cone ERG was more severely reduced than rod ERG.

CaseNotHPOs: HP:0007769 (Peripheral retinal degeneration), HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and family members were not genotyped outside of the RPGR locus.

CaseMethod1: Sanger sequencing of exon 15 of RPGR

CaseMethod2: N/A

CaseGenotypingMethod: The proband and family members were genotyped by Sanger sequencing of exon 15 of RPGR, but not by genome-wide methods.

Variant: The proband harbors the NM_001034853.2(RPGR):c.2847_2848inv (p.Glu949_Glu950delinsAspTer) variant in the hemizygous state.

ClinVar: 9917

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

VariantEvidence: NM_001034853.2(RPGR):c.2847_2848inv (p.Glu949_Glu950delinsAspTer) is an indel in the final exon (exon 15) that introduces a premature stop codon. Although it is not predicted to trigger nonsense-mediated decay, it at least disrupts ~18% of the C-terminus of the protein product.

CaseAddInfo: The proband is a member of Family A (shown in Figure 1), which includes four other affected genotype-positive males and four carrier females who showed RPE abnormalities.

CasePMIDs: N/A

PMID: 19610097

Gene: GPR143

HGNC: 20145

Disease: X-linked recessive ocular albinism

MONDO: 0021019

InheritancePattern: X-linked recessive

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

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

PMID: 31058429

GeneName: GNAT2

HGNC: 4394

Disease: achromatopsia 4

MonDO ID: MONDO_0013465

Inheritance: autosomal recessive

Case#: Manes_2013_Family_NA1863_Proband_II:1, male, age between 25 and 45 years at time of report, national origin reported as Italian

CasePresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0030631 (Hyperautofluorescent macular lesion), HP:0008179 (Decreased Arden ratio of electrooculogram, specifically 1.53 and 1.61 in each eye), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)

CaseHPOFreeText: The patient has been diagnosed with vitelliform macular dystrophy, and has very mildly reduced visual acuity (20/22).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

Variant: The proband harbors the NM_001563.4(IMPG1):c.807+1G>T variant in the homozygous state.

ClinVar: 162134

gnomAD: The NM_001563.4(IMPG1):c.807+1G>T variant was found in gnomAD v2.1.1 at a frequency of 0.000008855 (1/112932) in the European non-Finnish population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76728434-C-A

VariantEvidence: NM_001563.4(IMPG1):c.807+1G>T is a canonical splice site variant in intron 7 that does not have evidence confirming an impact on the gene product.

CaseAddInfo: The proband has a similarly affected younger sister who shares the same genotype. Parents are clinically unaffected heterozygous carriers but each harbor tiny extramacular deposits in the fundus. Consanguinity is reported in this family.

CasePMIDs: N/A

FamilyLabel: Manes_2013_Family_MTP327

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

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

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: The family is reportedly French.

Ethnicity: Not specifically described

Race: Not specifically described

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

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

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

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

Affected: 8 genotyped

Unaffected: 4 genotyped

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

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

eLOD: N/A

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

ProbandLabel: Manes_2013_Family_MTP327_Proband

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

ClinVar ID: 162133

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

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

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

FamilyPMIDs: N/A

Case#: Bech-Hansen_2000_Family_R5_proband, male, age and race not mentioned, national origin in the United States

CasePresentingHPOs: HP:0030640 (Complete congenital stationary night blindness), HP:0030469 (Abnormal dark-adapted electroretinogram)

CaseHPOFreeText: At least one of two ERG abnormalities were observed in each affected family member; absence of rod psychophysical dark adaptation and/or absence of rod ERG with low-intensity blue flash.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Linkage analysis was originally performed in PMID: 2574143 using 17 X-chromosomal restriction fragment length polymorphism markers.

CaseMethod1: Agarose gel electrophoresis of the relevant PCR product to monitor segregation in the proband and family members

CaseMethod2: Sanger sequencing of PCR amplified exons from NYX

CaseGenotypingMethod: Linkage analysis was initially performed in PMID: 2574143 using 17 X-chromosomal restriction endonuclease-based markers. The proband and family members were then subjected to gel electrophoresis analysis of PCR products and Sanger sequencing to identify the variant.

Variant: The proband harbors the NM_001378477.3(NYX):c.70_93del (p.Arg24_Ala31del) variant on the X chromosome.

ClinVar: 99841

gnomAD: NM_001378477.3(NYX):c.70_93del (p.Arg24_Ala31del) has a maximum allele frequency of 0.0001018 (1/9823, with no males or homozygous females) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/X-41332781-GGCCTGCGCCCGCGCTTGTCCCGCC-G

VariantEvidence: This in-frame deletion variant does not have experimental evidence of impact on the protein product, but is a recurrent variant observed in multiple apparently unrelated families (PMID: 2574143 and Figure 5 from this paper).

CaseAddInfo: Family phenotypes were described in PMID: 2574143.

CasePMIDs: PMID: 2574143

FamilyLabel: Bech-Hansen_2000_Family_R5

Family#PresentingHPOs: HP:0030640 (Complete congenital stationary night blindness), HP:0030469 (Abnormal dark-adapted electroretinogram)

Family#PresentingHPOFreeText: At least one of two ERG abnormalities were observed in each affected family member; absence of rod psychophysical dark adaptation and/or absence of rod ERG with low-intensity blue flash

FamilyNotHPOs: N/A

CountryOrigin: The United States

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Linkage analysis was originally performed in PMID: 2574143 using 17 X-chromosomal restriction fragment length polymorphism markers.

Family#Method1: Agarose gel electrophoresis of the relevant PCR product to monitor segregation in family members

Family#Method2: Sanger sequencing of PCR amplified exons from NYX

Family#GenotypingMethod: Linkage analysis was initially performed in PMID: 2574143 using 17 X-chromosomal restriction endonuclease-based markers. Family members were then subjected to gel electrophoresis analysis of PCR products and Sanger sequencing to identify the variant.

Affected: 4

Unaffected: 5

Segregations: 6 segregations (all consistent) among genotyped individuals are shown in this paper (pedigree in Fig. 3).

PublishedLOD: 7.35 (in PMID: 2574143, combined from 7 families)

eLOD: 1.8

AddSegregationInfo: N/A

ProbandLabel: Bech-Hansen_2000_Family_R5_proband

Variant: Affected male family members harbor the NM_001378477.3(NYX):c.70_93del (p.Arg24_Ala31del) variant on the X chromosome.

ClinVar: 99841

gnomAD: NM_001378477.3(NYX):c.70_93del (p.Arg24_Ala31del) has a maximum allele frequency of 0.0001018 (1/9823, with no males or homozygous females) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/X-41332781-GGCCTGCGCCCGCGCTTGTCCCGCC-G

FamilyAddInfo: Family phenotypes were described in PMID: 2574143.

FamilyPMIDs: PMID: 2574143

PMID: 11062471

Gene: NYX

HGNC: 8082

Disease: Congenital stationary night blindness 1A

MONDO: 0010690

InheritancePattern: X-linked recessive

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

Penetrance: Penetrance is thought to be complete.

PMID: 10471510

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#: Allen_2003_Familly_X03_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.37+1G>C (p.=) variant on the X chromosome.

CAID: CA412988630

gnomAD: NM_022567.2(NYX):c.37+1G>C (p.=) was not found in gnomAD.

VariantEvidence: This splice site variant disrupts a canonical splice site between the two coding exons (exon 2 and exon 3), and is therefore predicted to disrupt the protein product.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Allen_2003_Familly_X04_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.339_353del (p.Glu114_Ala118del) variant on the X chromosome.

CAID: CA2573050968

gnomAD: NM_022567.2 (NYX):c.339_353del (p.Glu114_Ala118del) was not found in gnomAD.

VariantEvidence: NM_022567.2:c.339_353del is an in-frame deletion variant that removes 5 amino acids from the center of the polypeptide sequence. It is a recurrent variant reported here in multiple apparently unrelated British families (X04 and X06).

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Parry_2009_Family_MEP49_patient_IV:5, male, age not specified, family origin reported to be Pakistani

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0007401 (Macular atrophy), HP:0000580 (Pigmentary retinopathy), HP:0007769 (Peripheral retinal degeneration), HP:0008323 (Abnormal light- and dark-adapted electroretinogram)

CaseHPOFreeText: The proband was diagnosed with cone-rod dystrophy, with family showing autosomal recessive mode of inheritance. Most affected members of the proband's family had white patches around the optic disc and in the posterior pole.

CaseNotHPOs: HP:0000639 (Nystagmus), HP:0000613 (Photophobia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and his family have been initially genotyped by autozygosity mapping with both 10k and 250k Affymetrix SNP arrays and microsatellite markers.

CaseMethod1: Autozygosity mapping

CaseMethod2: Sanger sequencing

CaseGenotypingMethod: The proband and his family have been initially genotyped by autozygosity mapping with both 10k and 250k Affymetrix SNP arrays and microsatellite markers. Sanger sequencing of the ADAM9 locus then identified the variants.

Variant: The proband harbors the NM_003816.3(ADAM9):c.766C>T (p.Arg256Ter) variant in the homozygous state.

ClinVar: 6877

gnomAD: This variant is found in gnomAD v2.1.1 at a frequency of 0.00003267 (1/30608) in the South Asian population, with no homozygotes. https://gnomad.broadinstitute.org/variant/8-38880696-C-T

VariantEvidence: NM_003816.3(ADAM9):c.766C>T (p.Arg256Ter) is a nonsense variant in exon 9 of 21, and is therefore predicted to result in nonsense-mediated decay.

CaseAddInfo: The proband's family is known to be consanguineous, with the parents being first cousins (pedigree shown in Figure 2).

CasePMIDs: N/A

PMID: 19801642

Gene: PDE6C

HGNC: 8787

Disease: cone dystrophy 4

MONDO: 0013129

InheritancePattern: recessive

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

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

PMID: 25766588

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

FamilyLabel: Gliem_2015_Family_1

Family#PresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy), HP:0030605 (Abnormal indocyanine green angiography), HP:0012508 (Metamorphopsia), HP:0000662 (Nyctalopia), HP:0011506 (Choroidal neovascularization)

FamilyHPOFreeText: Onset in the fifth or sixth decade of life with dark adaptation problems or metamorphopsia, Indocyanine green angiography showing late-phase hypofluorescence early in the disease process, central and midperipheral atrophy, reduced choroidal thickness, yellow deposits in older affected family members, CNV in some patients but not others

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Germany

Family#PreviousTesting: N/A

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

Affected: 7

Unaffected: 1

Segregations: 7

PublishedLOD: N/A

eLOD: 2.1

AddSegregationInfo: N/A

ProbandLabel: Gliem_2000_Family_1_patient_II.1

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

CAID: CA411540328

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

FamilyLabel: Gliem_2015_Family_2

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

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

FamilyNotHPOs: HP:0000662 (Nyctalopia)

FamilyNotHPOFreeText: Dark adaptation problems, early onset of symptoms

CountryOrigin: Germany

Family#PreviousTesting: N/A

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

Affected: 6

Unaffected: 2

Segregations: 12

PublishedLOD: N/A

eLOD: 2.1

AddSegregationInfo: N/A

ProbandLabel: Gliem_2000_Family_2_patient_V.1

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

CAID: CA411540365

gnomAD: Variant is absent from gnomAD.

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

FamilyPMIDs: PMID:25390527

Case#: GC17880, Presumed F, Age of Report: 37 y.o. Ethnicity: N/A.

CasePresentingHPOs: HP:0030786 (Photopsia), HP:0000662 (Nyctalopia), HP:0001123 (Visual field defect/field defects), HP:0000585 (Band keratopathy/Left band keratopathy), HP:0007703 (Abnormality of retinal pigmentation)

CaseHPOFreeText: The proband was diagnosed with simplex RP and was the second of three siblings born to first-cousin parents with no family history of eye disease, underwent WES revealing 21,404 coding variants.

Other reported symptoms include: Irregular pigmented lesions in periphery, foveal/parafoveal cysts.

Fields to confrontation age 36 years less than 30 degrees.

Proband also was diagnosed with left band keratopathy, Wolf-Parkinson White syndrome, 4 miscarriages.

CaseNotHPOs: HP:0005268 (Miscarriage), HP:0001716 (Wolff-Parkinson-White syndrome)

CaseNotHPOFreeText: N/A.

CasePreviousTesting: Sanger sequencing of CRB1.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_001130955.1:c.1617+5G>A.

ClinVar ID: 417758.

gnomAD: Frequency: 0.000003099. Link: https://gnomad.broadinstitute.org/variant/19-7456408-G-A?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: CA16616865.

CasePMIDs: N/A.

Case#: GC3626, M, Age of Report: 51 y.o., Ethnicity: N/A.

CasePresentingHPOs: HP:0030786 (Photopsia), HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0000543 (Optic disc pallor/pale discs), HP:0011505 (Cystoid macular edema), HP:0031527 (Retinal edema), HP:0011531 (Vitritis/Vitritis cells), HP:0007703 (Abnormality of retinal pigmentation)

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, following a previous diagnosis of Stargardt's macular dystrophy almost 1 decade earlier. First onset of night vision loss was reportedly in his teens.

Other reported symptoms include: Irregular pigmented lesions in periphery, pale discs, cystoid macular edema, peripheral telangiectasia with some retinal edema and vitreous cells, possible para-arteriolar sparing.

Goldmann visual fields age 29: ring scotoma at 30 degrees, binocular Esterman age 36: central 20 degrees only retained.

Also diagnosed with L Fuch’s heterochromic cyclitis.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: Sanger sequencing of CRB1.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WGS.

Variant: Variant 1: NM_001367823.1:c.3196G>T. Variant 2: NM_001367823.1:c.3302_3325del.

ClinVar ID: Variant 1: 417757. Variant 2: 417756.

gnomAD: Variant 1: Frequency: 6.524e-7 (Allele Frequency). Link: https://gnomad.broadinstitute.org/variant/19-7467400-G-T?dataset=gnomad_r4. Variant 2: N/A.

VariantEvidence: N/A.

CaseAddInfo: Variant 1: CA16616864. Variant 2: CA16616863.

CasePMIDs: N/A.

Case#: GC18203, F, Age of Diagnosis: 37 y.o., Ethnicity: N/A.

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0000543 (Optic disc pallor/pale discs), HP:0011505 (Cystoid macular edema), HP:0007703 (Abnormality of retinal pigmentation)

CaseHPOFreeText: The proband was diagnosed with simplex retinitis pigmentosa. The proband is the second of two siblings born to unrelated parents with no family history of eye disease.

At 20 yrs of age, the proband developed the following symptoms: reduced acuity, mild nyctalopia and blind spots.

Other reported symptoms include irregular peripheral pigment, pale discs, cystoid macular edema, vitreous opacities, attenuated sheathed vessels, peripheral retinal exudate.

Octopus visual fields age 36 central 20-30 degrees retained on R , 30-50 degrees on L, age 37 24-2 central scotomas, fields now constricted to 15 degrees each eye.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: Sanger sequencing of CRB1.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WGS.

Variant: Variant 1: NM_001367823.1:c.808A>G. Variant 2: NM_001367823.1:c.2560C>T.

ClinVar ID: Variant 1: N/A. Variant 2: 417755.

gnomAD: Variant 1: Frequency: 0. Link:https://gnomad.broadinstitute.org/variant/19-7382877-A-G?dataset=gnomad_r4. Variant 2: Frequency: 0.000002920. Link: https://gnomad.broadinstitute.org/variant/19-7462259-C-T?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: Variant 1: CA403164517. Variant 2: CA16616862.

CasePMIDs: N/A

PMID: 27203721

Gene: CLN5

HGNC: 2076

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

MONDO: 0009745

InheritancePattern: Autosomal Recessive

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

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

Case#: Patient 2, male, 33 (at report), 6 years old at onset

CaseHPOs: HP:0000613, HP:0007663, HP:0000551 (photophobia, reduced visual acuity, color vision defect)

CaseHPOsFreeText: BCVA LogMAR 1 for both eyes, refractive error −4.25 sph −2.00 cyl/180° D in right eye and −4.00 sph −2.50 cyl/30° D in left eye. The fundus exam showed normal optic disk, signs of foveal atrophy, and “salt and pepper” peripheral retinopathy. Fundus autofluorescence revealed a dark central area due to the absence of the RPE surrounded by an unusual hyperfluorescent perifoveal ring in both eyes while infrared retinography showed foveal atrophy. OCT imaging revealed a marked reduction of the foveal thickness associated with a photoreceptor layer disruption (Figure 3). Goldmann visual field test showed central scotoma with a mild peripheral constriction.

CaseNotHPOs:

CasePreviousTesting: None mentioned but note that, in this study, DNA from all patients was analyzed by CORD NGS panel.

CaseMethod1: NGS panel

CaseGenotypingMethod: CORD NGS panel - ABCA4, ADAM9, AIPL1, C8orf37, CFAP410 (C21orf2), CACNA1F, CACNA2D4, CDHR1, CEP78, CNGA3, CRX, DRAM2, GUCA1A, GUCY2D, UNC119, IFT81, KCNV2, PDE6C, PITPNM3, POC1B, PROM1, PRPH2, RAB28, RAX2, RIMS1, RPGR, RPGRIP1, SEMA4A, TTLL5.

Variant: c.37del (p.Leu13Ter) homozygous

ClinVar: N/A

CAID: CA2860243

gnomAD: The highest MAF in gnomAD v2.1.1 is 0.00003019 in European non-Finnish (no homozygotes in any population)

VariantEvidence: The variant would either result in nonsense-mediated mRNA decay, or retain few of the structural elements required for correct folding, causing degradation.

CaseAddInfo: Patient 3 is the affected sister of Patient 2. She is affected but has a milder phenotype. The father of these individual is unaffected and heterozygous for the variant. No details are provided about the mother.

ExperimentName: IFT140 variant rescue in Ift140 knockout cells

RescueCellLine: Mouse Inner Medullary Collecting Duct 3 (mIMCD3) cells

RescueCellEFO: EFO:0002887 (mouse cell line), EFO:0001643 (kidney-derived cell line)

GeneAlteration: The cell line was subjected to CRISPR-based knockout of endogenous IFT140 (targeting exon 8).

RescueCellPhenotype: Ift140 knockout cells exhibited a complete inability to form cilia relative to the control rescued by overexpression of wild-type Ift140 (Figure 3b) and aberrant accumulation of the IFT-B protein IFT88 at the ciliary tip (Figure 3d).

RescueMethod: Transient transfection and over-expression of wild-type or variant IFT140 was used to rescue the cell phenotypes.

RescueEvidence: Wild-type IFT140 restored ciliogenesis in 11% of cells, while either variant restored ciliogenesis to 6%, despite the surprising continued absence of the frameshift variant at the protein level (Figure 3b). Wild-type IFT140 reduced the proportion of cells exhibiting IFT88 accumulation at the ciliary tip to 23%, while either variant partially reduced IFT88 localization to the ciliary tip to 50% or 56% (Figure 3d).

RescueCellVariant: The variants used for the rescue experiment were NM_014714.3(IFT140):c.992_993dup (p.Tyr332Valfs*18) (cannot be registered manually) and NM_014714.3:c.2767T>G (p.Tyr923Asp) (CA394227092).

PMID: 32265257

Gene: IMPG1

HGNC: 6055

Disease: vitelliform macular dystrophy 4

MONDO: 0014508

InheritancePattern: semi-dominant

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

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

PMID: 32265257

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: 18697795

Gene: GPR143

HGNC: 20145

Disease: X-linked recessive ocular albinism

MONDO: 0021019

InheritancePattern: X-linked recessive

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

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

PMID: 14507859

Gene: NYX

HGNC: 8082

Disease: Congenital stationary night blindness 1A

MONDO: 0010690

InheritancePattern: X-linked recessive

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

Penetrance: Penetrance is thought to be complete.

PMID: 7710395

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).

Case#: Bandah-Rozenfeld_2010_MOL0732_proband, female, age 63 years at time of diagnosis, ethnic origin reported as Israeli Christian Arab

CasePresentingHPOs: HP:0008002 (Abnormality of macular pigmentation), HP:0030613 (Abnormal foveal morphology on macular OCT), HP:0030557 (Best corrected visual acuity 0.4 LogMAR), HP:0000603 (Central scotoma), HP:0031729 (Moderate hypermetropia), HP:0000518 (Cataract)

CaseHPOFreeText: The patient has been diagnosed with mild maculopathy. "Abnormal foveal morphology" refers to elevation of the photoreceptor layer in foveal region by OCT analysis. The "cataract" specifically refers to mild nuclear sclerosis.

CaseNotHPOs: HP:0000512 (Abnormal electroretinogram), HP:0000551 (Color vision defect)

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.370T>C (p.Phe124Leu) variant in the homozygous state.

ClinVar: 3550

gnomAD: The NM_016247.4(IMPG2):c.370T>C (p.Phe124Leu) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.0001318 (17/129010, with 0 homozygotes) in the European (non-Finnish) population. https://gnomad.broadinstitute.org/variant/3-101023121-A-G

VariantEvidence: NM_016247.4(IMPG2):c.370T>C (p.Phe124Leu) is a missense variant in exon 3 of 19 that does not have evidence of impact on the protein product.

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

CasePMIDs: A publication by a separate group referred to this case as autosomal recessive vitelliform macular dystrophy, but did not indicate the existence of any additional details about the case (PMID: 25085631).

PMID: 27720922

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.

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

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

InteractionType: Physical

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

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

FamilyLabel: Gong_1996_Three_Families

Family#PresentingHPOs: N/A

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

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: The three families are reportedly of Finnish, South African, and Italian descent, respectively.

Ethnicity: Not specifically described

Race: Not specifically described

Family#PreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1).

Family#Method1: Genome-wide linkage analysis

Family#Method2: Further linkage analysis with additional markers around a strong candidate marker

Family#GenotypingMethod: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (Fig. 1). Further linkage testing with additional markers around a strong candidate marker yielded a LOD score of 5.99 for Dl1S987. The region consisted of a 13-cM genetic interval on chromosome 11q12-13.

Affected: 7 genotyped

Unaffected: 5 genotyped

Segregations: 5 segregations are shown by the three pedigrees in Figure 1.

PublishedLOD: 5.99 (for the Dl1S987 marker)

eLOD: N/A

AddSegregationInfo: While only one of the families would individually be eligible for inclusion in segregation evidence using an estimated LOD score, the published LOD score is sufficient for their inclusion.

ProbandLabel: N/A (Probands have been incorporated into the later Gong 2001 publication and will be scored in connection to that article.)

Variant: The affected family members harbor three different variants, each in the homozygous state.

ClinVar: N/A

gnomAD: N/A

VariantEvidence: N/A

FamilyAddInfo: All three families are reportedly consanguineous.

FamilyPMIDs: N/A

Case#: Mykykyn_2002_Proband_D, gender not specified, age not described, family origin reported as from Turkish

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.851del (p.Tyr284fs) variant in the homozygous state.

ClinVar ID: 12146

gnomAD: The variant is found in gnomAD v2.1.1 at a frequency of 0.00001758 (2 alleles out of 113768 total alleles, with 0 homozygotes) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-66290946-TA-T?dataset=gnomad_r2_1

VariantEvidence: NM_024649.5(BBS1):c.851del (p.Tyr284fs) is a frameshift variant in exon 10 of 17 that is predicted to trigger nonsense mediated decay or to at least truncate the C-terminal 52% of the protein product.

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

CasePMIDs: N/A

Case: Weber_1994_Family_B_Patient_V-1, male, country of origin Canada (PMID:7920634), genealogy indicating Irish descent (PMID: 2695876)

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo:

CasePresentingHPOs: HP:0030506 (Yellow/white lesions of the retina), HP:0030604 (Abnormal fundus fluorescein angiography), HP:0011506 (Choroidal neovascularization), HP:0000533 (Chorioretinal atrophy), HP:0200070 (Peripheral retinal atrophy)

CaseHPOFreeText: Yellow/white lesions were present within fundus specifically. Angiography showed mottled hypofluorescence. Chorioretinal atrophy was described as showing peripheral progression.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Linkage analysis using short tandem repeat markers derived from genomic regions shown to contain loci involved in macular degeneration (PMID:7920634).

GenotypingMethod: Sanger sequencing

PreviouslyPublished: PMID:2695876, PMID:7920634

SupplementalData: N/A

Variant: The variant is NM_000362.5(TIMP3):c.610A>T, p.Ser204Cys, which was first referred to in PMID:7894485 as "Ser181Cys" (due to the removal of a 23-amino acid N-terminal signal peptide from the polypeptide sequence) but encodes Ser204Cys in the full/updated polypeptide sequence.

ClinVar: 12676

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure.

PMID: 28676737

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.

FamilyLabel: Naessens_2019_Family_1

FamilyPresentingHPOs: HP:0011510 (Drusen)

FamilyHPOFreeText: Relatively late onset of phenotypes between ages 49 and 74. Drusen / deposits were universal except for 3 individuals between the ages of 37 and 47.

**FamilyNotHPOs: N/A

FamilyNotHPOFreeText: Pulmonary involvement

CountryOrigin: Belgium

Family#PreviousTesting: Yes, SSCP and Sanger sequencing were both previously performed (PMID:10873973), but results were negative (no TIMP3 variant found).

Family#Method1: SSCP of all five exons, plus the promoter and 3'UTR of TIMP3

Family#Method2: Sanger sequencing of PCR-amplified exon 5 of TIMP3

Family#GenotypingMethod: PCR amplification of all 5 coding exons of TIMP3, followed by Sanger sequencing

Affected: 18

Unaffected: 29

Segregations: 23

PublishedLOD: N/A

eLOD: 6.9

AddSegregationInfo: N/A

ProbandLabel: Naessens_2019_Family_1_patient_IV:31

Variant: The variant is NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys), a missense variant predicted to introduce a new cysteine-encoding codon into exon 1.

ClinVar: 843268

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: Family was previously genotyped in PMID:10873973, but SSCP analysis of all 5 exons and Sanger sequencing of exon 5 were not sufficient at that time to detect the variant in exon 1.

FamilyPMIDs: PMID:10873973

Case: Naessens_2019_Family_1_Patient_IV:31, female, age of onset 51 years old, country of origin Belgium

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: Familial variant appears to come from a founder mutation shared by other families in Belgium and northern France with a distant common ancestor.

CasePresentingHPOs: HP:0011510 (Drusen), HP:0000613 (Photophobia), HP:0000572 (Visual loss)

CaseHPOFreeText: Relatively late onset of phenotypes (at age 51, presenting with photophobia). Drusen was described as widespread around the vascular arcades.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: Pulmonary involvement

CasePreviousTesting: Yes, SSCP and Sanger sequencing were both previously performed (PMID:10873973), but results were negative (no TIMP3 variant found).

CaseMethod1: SSCP of all five exons, plus the promoter and 3'UTR of TIMP3

CaseMethod2: Sanger sequencing of PCR-amplified exon 5 of TIMP3

GenotypingMethod: PCR amplification of all 5 coding exons of TIMP3, followed by Sanger sequencing

PreviouslyPublished: PMID:10873973

SupplementalData: Supplementary Table S3 from this paper (PMID: 30668888) provides some of the proband phenotype details.

Variant: The variant is NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys), a missense variant predicted to introduce a new cysteine-encoding codon into exon 1.

ClinVar: 843268

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure. Patient fibroblasts reveal no change in expression of the variant at the mRNA level, no dimerization of the variant under non-reducing conditions, and no defect in its localization to the ECM. Variant showed a minor increase in glycosylation. An in vitro transcription and translation study found that the variant forms an aberrant intramolecular disulfide bond between the introduced Ser38Cys residue and Cys36 of TIMP3 (Figure 7). Aberrant intramolecular disulfide bonding caused by this variant would be consistent gain-of-function and an autosomal dominant mechanism of inheritance.

Case: Naessens_2019_Family_3_Patient_II:1, male, age of onset 53 years old, country of origin Belgium

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: Family member genotypes and phenotypes are not available, but variant appears to come from a founder mutation shared by other families in Belgium and northern France with a distant common ancestor.

CasePresentingHPOs: HP:0011510 (Drusen), HP:0000572 (Visual loss), HP:0007401 (Macular atrophy), HP:0011506 (choroidal neovascularization), HP:0007703 (Abnormality of retinal pigmentation)

CaseHPOFreeText: Relatively late onset of phenotypes (at age 53, presenting with nyctalopia). Drusen was described as calcified around the vascular arcades. CNV was active. Macular atrophy was patchy. Intraretinal pigment migration was observed from midperiphery towards periphery.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: Pulmonary involvement

CasePreviousTesting: N/A

GenotypingMethod: PCR amplification of all 5 coding exons of TIMP3, followed by Sanger sequencing

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S3 from this paper (PMID: 30668888) provides some of the proband phenotype details.

Variant: The variant is NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys), a missense variant predicted to introduce a new cysteine-encoding codon into exon 1.

ClinVar: 843268

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure. Patient fibroblasts reveal no change in expression of the variant at the mRNA level, no dimerization of the variant under non-reducing conditions, and no defect in its localization to the ECM. Variant showed a minor increase in glycosylation. An in vitro transcription and translation study found that the variant forms an aberrant intramolecular disulfide bond between the introduced Ser38Cys residue and Cys36 of TIMP3 (Figure 7). Aberrant intramolecular disulfide bonding caused by this variant would be consistent gain-of-function and an autosomal dominant mechanism of inheritance.

PMID: 10191083

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

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

ExperimentName: Nyx localization to the post-synaptic side of both synaptic layers of the zebrafish retina

TissueExpression: UBERON:0001790 (Outer plexiform layer of retina), UBERON:0001795 (Inner plexiform layer of retina

ExpressionEvidence: Nyx was detected by antibody staining of zebrafish retinal sections and was found to localize strongly to both synaptic layers (the outer plexiform layer and inner plexiform layer) but not the outer nuclear layer or inner nuclear layer (Fig. 5A). Lack of co-localization between Nyx and either SV2 or PSD-95 (two presynaptic markers) confirmed that Nyx is specifically post-synaptically localized (Figs. 5C, 6A). This was further confirmed by the detection of Nyx-labeled second-order neuron dendrites invaginating into presynaptic cone pedicles (Figs. 6B and 6C). This data is highly compatible with the findings of a separate mouse experiment (PMID: 17881478) showing that Nyx transgene expression in the dendritic tips of retinal depolarizing bipolar cells rescues the phenotype of Nyx-deficient mice.

Selection B- Gene function is consistent with phenotype.

GOterm: GO:0008191 (metalloendoproteinase inhibitor activity)

FunctionalEvidence: The functional evidence consists of an electrophoretic assay in which the 21-kDa chicken ortholog of human TIMP3 shows inhibitory activity towards a metalloproteinase.

FunctionalHPO: Abnormal extracellular matrix turnover in the inner aspect of Bruch's membrane

PhenotypeEvidence: This metalloproteinase inhibitor activity and ECM localization of the gene product indicate that it functions in ECM remodeling, balancing the activity of matrix metalloproteinases. This is consistent with the disease phenotype of abnormal thickening of the inner aspect of Bruch's membrane (PMID:11879143). The inhibitor evidence is shown in Figure 2B, where a 21-kDa band protects a gelatin substrate from enzymatic metalloproteinase activity. The purification of the gene product from the extracellular matrix is depicted in Figure 1. A later study showed that the human ortholog of this chicken gene is the TIMP3 gene, mapped to the region on chromosome 22 between q12.1-q13.2 (PMID:8188246).

PMID: 1845973

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

Case#: Georgiou_2024_Family_NY01_Proband_P10, female, reported at age 56 years, family origin not reported

CasePresentingHPOs: HP:0011003 (High myopia), HP:0030558 (Best corrected visual acuity 0.5 LogMAR), HP:0000518 (Cataract)

CaseHPOFreeText: BCVA began at 0.51 logMAR and progressed to 0.54 logMAR. The proband had posterior chamber intraocular lenses. Myopia developed by age 7 years.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel / WES / WGS

CaseMethod2: Sanger sequencing of RBP3

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

Variant: The individual harbors the NM_002900.3(RBP3):c.2824C>T (p.Gln942Ter) variant in the homozygous state.

ClinVar ID: 1069291

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.00001332 (1 / 75072) in the African / African-American population https://gnomad.broadinstitute.org/variant/chr10-47351308-C-T?dataset=gnomad_r4

VariantEvidence: NM_002900.3(RBP3):c.2824C>T (p.Gln942Ter) is a nonsense variant within exon 1 of 4 that is predicted to trigger nonsense-mediated decay.

CaseAddInfo: Potential consanguinity within the proband's family and their geographic origin have not been commented on.

CasePMIDs: N/A

Case#: Georgiou_2024_Family_GC29680_Proband_P09, female, reported at age 30 years, family origin reported as from Bangladesh

CasePresentingHPOs: HP:0011003 (High myopia), HP:0030558 (Best corrected visual acuity 0.5 LogMAR)

CaseHPOFreeText: BCVA began at 0.39 logMAR and progressed to 0.54 logMAR.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel / WES / WGS

CaseMethod2: Sanger sequencing of RBP3

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

Variant: The individual harbors the NM_002900.3(RBP3):c.3399T>G (p.Tyr1133Ter) variant in the homozygous state.

ClinVar ID: 3675731

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.00001098 (1 / 91070) in the South Asian population https://gnomad.broadinstitute.org/variant/chr10-47357112-T-G?dataset=gnomad_r4

VariantEvidence: NM_002900.3(RBP3):c.3399T>G (p.Tyr1133Ter) is a nonsense variant within exon 4 of 4 that is predicted to trigger nonsense-mediated decay.

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

CasePMIDs: N/A

Case#: Xiao_2023_Family_2_Proband, male, age 0.5 years, family origin reported as from Yi ethnic group from Yunnan, China

CasePresentingHPOs: Infantile onset HP:0003593, Pigmentary retinopathy HP:0000580, Mild myopia HP:0025573

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa with onset at 0.3 years of age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband consisted of whole exome sequencing.

CaseMethod1: whole exome sequencing

CaseMethod2: Sanger sequencing of the coding regions of PRPF4

CaseGenotypingMethod: Genotyping of the proband initially consisted of whole exome sequencing, followed by Sanger sequencing of the coding regions of PRPF4.

Variant: The proband harbors the NM_001244926.2(PRPF4):c.1270G>A (p.Gly424Ser) variant in the heterozygous state.

ClinVar ID: 1395419

gnomAD: The NM_001244926.2(PRPF4):c.1270G>A (p.Gly424Ser) variant is found in gnomAD v4.1.0 at a frequency of 0.00008729 (103 alleles / 1180028 total alleles, with 0 homozygotes) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/9-113290914-G-A?dataset=gnomad_r4

VariantEvidence: NM_001244926.2(PRPF4):c.1270G>A (p.Gly424Ser) is a missense variant with no direct evidence of an abnormal impact on the PRPF4 protein.

CaseAddInfo: The proband has apparently unaffected parents.

CasePMIDs: N/A

Case#: Al-khuzaei_2020_Patient_III, female, 10 years old at presentation of symptoms, 16 years old at time of report, racial origin indicated as Caucasian

CasePresentingHPOs: Photophobia HP:0000613, Photopsia HP:0030786, Nyctalopia HP:0000662, Constriction of peripheral visual field HP:0001133, Yellow/white lesions of the macula HP:0030500, Hyperautofluorescent retinal lesion HP:0025158, Photoreceptor layer loss on macular OCT (ellipsoid zone loss with preservation of the central retina) HP:0030609, Undetectable dark-adapted electroretinogram HP:0030474, Abnormal timing of light-adapted single flash electroretinogram HP:0030482, Abnormal amplitude of light-adapted single flash electroretinogram HP:0030481, Abnormal dark-adapted dim flash electroretinogram HP:0030471, Abnormal amplitude of dark-adapted dim flash electroretinogram HP:0030476, Ring scotoma HP:0030529, Patchy atrophy of the retinal pigment epithelium HP:0007791

CaseHPOFreeText: The proband has a diagnosis of enhanced S-cone sensitivity.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was performed by next-generation sequencing with a 111-gene panel.

CaseMethod1: Next-generation sequencing with a 111-gene panel.

CaseMethod2: Sanger sequencing of NR2E3

CaseGenotypingMethod: Genotyping was performed by next-generation sequencing with a 111-gene panel, followed by Sanger sequencing of NR2E3.

Variant: The individual harbors the maternal NM_014249.4(NR2E3):c.119-2A>C and paternal NM_014249.4(NR2E3):c.639_640insT (p.Pro214fs) variants in the compound heterozygous state.

ClinVarID: 191059, 1455685

gnomAD: The NM_014249.4(NR2E3):c.119-2A>C variant is found in gnomAD version 4.1.0 at a frequency of 0.001359 in the Ashkenazi Jewish population and 0.0007992 in the European (non-Finnish) population (919 / 1,149,942), with no homozygotes observed. https://gnomad.broadinstitute.org/variant/chr15-71811481-A-C?dataset=gnomad_r4 The NM_014249.4(NR2E3):c.639_640insT (p.Pro214fs) variant is found in gnomAD v4.1.1 at a frequency of 0.000008846 (1 allele / 113,042 total alleles) in the European (non-Finnish) population, with 0 homozygotes. https://www.ncbi.nlm.nih.gov/clinvar/variation/1455685/

VariantEvidence: NM_014249.4(NR2E3):c.119-2A>C is a canonical splice acceptor site variant adjacent to exon 2 of 6, which is an out-of-frame exon that could potentially trigger nonsense-mediated decay if skipped. This paper shows mRNA evidence that the variant triggers exon 2 skipping and introduces a premature stop codon in exon 3. NM_014249.4(NR2E3):c.639_640insT (p.Pro214fs) is a frameshift variant in exon 5 of 8 that introduces a premature stop codon and is predicted to trigger nonsense-mediated decay.

CaseAddInfo: The proband has unaffected heterozygous carrier parents.

CasePMIDs: N/A

PMID: 16989765

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

Case#: Bernal_2008_Proband_B-256, male, age 13 years at time of report, national origin from Spain

CasePresentingHPOs: Nyctalopia HP:0000662, Progressive visual loss HP:0000529, Reduced visual acuity HP:0007663, Retinoschisis HP:0030502, Nummular pigmentation of the fundus HP:0030505, Undetectable light- and dark-adapted electroretinogram HP:0007688

CaseHPOFreeText: The proband has a diagnosis of Goldmann–Favre syndrome, and had peripheral retinoschisis and macular cysts in both eyes.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3.

Variant: The individual harbors the NM_014249.4(NR2E3):c.932G>A (p.Arg311Gln) variant in the homozygous state.

ClinVarID: 5532

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.003986 in the Ashkenazi Jewish population, with a 118 alleles / 29604 total alleles and 1 homozygote. The variant also has a frequency of 0.0009829 in the Admixed American population. https://gnomad.broadinstitute.org/variant/chr15-71813573-G-A?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.932G>A (p.Arg311Gln) is a missense variant that is a well-known founder and has been reported in patients from multiple studies with diverse presentations. The variant partially disrupts the ability of NR2E3 to form stable dimers (PMID: 11071390).

CaseAddInfo: The proband has two unaffected heterozygous parents.

CasePMIDs: N/A

Case#: Bernal_2008_Proband_B-316, female, age 47 years at time of report, national origin from Spain

CasePresentingHPOs: Nyctalopia HP:0000662, Progressive visual loss HP:0000529, Reduced visual acuity HP:0007663, Severe constriction of peripheral visual field HP:0030526, Undetectable light- and dark-adapted electroretinogram HP:0007688

CaseHPOFreeText: The proband has a diagnosis of retinitis pigmentosa, and had clusters of large, clumped pigment deposits in the midperiphery of both eyes.

CaseNotHPOs: Macular schisis HP:0011511

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3.

Variant: The individual harbors the NM_014249.4(NR2E3):c.1034_1038del (p.Ala344_Leu345insTer) variant in the homozygous state.

ClinVarID: 5534

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

VariantEvidence: NM_014249.4(NR2E3):c.1034_1038del (p.Ala344_Leu345insTer) is a frameshift variant that introduces a premature stop codon in exon 7 of 8 and is predicted to trigger nonsense-mediated decay.

CaseAddInfo: The proband has two affected siblings who share the same homozygous genotype and one unaffected heterozygous sibling. Parents have not been genotyped, but were indicated as consanguineous.

CasePMIDs: N/A

ExperimentName: Patient iPSC-derived retinal organoids exhibit severe outer segment defects that can be rescued by CRISPR/Cas9-based editing.

RescuePatientCell: EFO:0004905 (induced pluripotent stem cell, differentiated into a retinal organoid)

GeneAlteration: The patient cells have inherited compound heterozygous variants in IMPG2, encoding either p.Tyr254Cys or a frameshift variant starting at codon 805.

RescuePhenotype: Patient iPSC-derived retinal organoids harboring these two variants exhibited almost complete failure to form an outer segment or an interphotoreceptor matrix during a 200-day period (Figure 2A), relative to control retinal organoids with CRISPR/Cas9-based editing / rescue of both variants (Figure 2D).

RescueMethod: CRISPR/Cas9-based editing was used to correct both variants.

RescueEvidence: Control retinal organoids with CRISPR/Cas9-based editing / rescue of both variants (Figure 2D) showed development of both the IPM and the outer segment, relative to the uncorrected retinal organoids (Figure 2A). This rescue argues for a role of IMPG2 in photoreceptor cell outer segment development / maintenance.

RescueVariants: NM_016247.4:c.761A>G (p.Tyr254Cys, CA353867908) and an undefined frameshift variant at codon 805, either NM_016247.4:c.2413del (p.Ala805LeufsTer8) or NM_016247.4:c.2414del (p.Ala805ValfsTer8).

ExperimentName: Mouse model of Trpm1 loss-of-function

NonHumanModel: Mus musculus

GeneAlteration: The mouse has homozygous disruption of the Trpm1 gene by targeted deletion of regions from exons 3, 4, and 5 (PMID: 19439586).

ModelPhenotype: HP:0007984 (Electronegative electroretinogram)

HumanPhenotype: HP:0000662 (Nyctalopia), HP:0000545 (Myopia), HP:0000572 (Visual loss), HP:0007984 (Electronegative electroretinogram)

ModelEvidence: The affected mice exhibit abnormal dark-adapted ERG with absent b-wave and normal a-wave (Figure 3), similar to the affected human patients. Retinal slices from these mice exhibit defects in chemically stimulated light responses (Figure 4), indicating that Trpm1 is required for generating the depolarizing light response in ON-bipolar cells.

ModelVariant: The model harbors a targeted deletion that does not have an equivalent / orthologous variant reported in human patients.

PMID: 8673101

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

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: Sanger sequencing of the RPGR locus

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

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

ClinVar: 98794

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

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

CaseAddInfo: The proband is a member of Family RP49.

CasePMIDs: N/A

Case#: Danciger_2001_Family_Patient_A, gender not specified, age 48 years at the time of the report, family origin reported to be Brazilian

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0001141 (Severely reduced visual acuity), HP:0007994 (Peripheral visual field loss), HP:0000545 (Myopia), HP:0007703 (Abnormality of retinal pigmentation), HP:0007843 (Attenuation of retinal blood vessels), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0000483 (Astigmatism), HP:0000523 (Subcapsular cataract)

CaseHPOFreeText: The proband was diagnosed with severe cone-rod dystrophy.

CaseNotHPOs: HP:0000543 (Optic disc pallor)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and his family have been initially genotyped by linkage mapping using short tandem repeat markers across the genome.

CaseMethod1: Linkage mapping using short tandem repeat markers

CaseMethod2: Sanger sequencing

CaseGenotypingMethod: The proband and his family have been initially genotyped by linkage mapping using short tandem repeat markers across the genome. Haplotype analysis was then performed within the linkage region. Finally, a subsequent publication on the same family sequenced 10 out of 34 genes within the linkage region and found homozygous variants in ADAM9 in particular (PMID: 19409519).

Variant: The affected family members harbor the NM_003816.3(ADAM9):c.1130+1G>A variant in the homozygous state.

ClinVar: 6876

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

VariantEvidence: The NM_003816.3(ADAM9):c.1130+1G>A variant is predicted to disrupt a canonical splice site in intron 11.

CaseAddInfo: The proband's family is known to be consanguineous, with the parents being second cousins.

CasePMIDs: PMID: 19409519

PMID: 11581183

Gene: ADAM9

HGNC: 216

Disease: cone-rod dystrophy 9

MONDO: MONDO:0013002

InheritancePattern: autosomal recessive

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

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

ExperimentName: Canine model of PDE6A loss-of-function

NonHumanModel: Canis lupus familiaris

GeneAlteration: Cardigan Welsh Corgi animals were found to develop retinal degeneration due to a homozygous 1-bp deletion variant at codon 616 that results in a frameshift and a premature stop codon (genotype previously reported in PMID: 10393029).

ModelPhenotype: HP:0030474 (Undetectable dark-adapted electroretinogram), HP:0000505 (Visual impairment), HP:0007843 (Attenuation of retinal blood vessels), HP:0030610 (Photoreceptor outer segment loss on macular OCT)

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 an Electronegative electroretinogram (HP:0007984) and Abnormal light-adapted electroretinogram (HP:0008275), (Figures 2, 3, and 4). Retinal degeneration (HP:0000546) was observed with outer nuclear photoreceptor layer thinning (HP:0030610, Figure 5). Photoreceptor outer segment loss is visible on macular OCT (Figure 6, Figure 7), particularly loss of rod photoreceptor cells.

ModelVariant: The model does not harbor a variant equivalent to one from the human patients, but rather has a naturally occurring frameshift variant disrupting Pde6a leading to full loss-of-function.

PMID: 31654038