PMID: 33546218

Gene: PROM1

HGNC: 9454

Disease: retinitis pigmentosa 41

MONDO: 0012796

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). The proportion of that incidence made up by the specific form caused by biallelic variants in PROM1 is not clear.

Penetrance: Known disease-causing alleles appear to be completely penetrant in the homozygous state, and for at least some heterozygous variants associated with other disease entities.

Selection B- Expression altered in patients:

ExperimentName: Detection of CLN5 mRNA and CLN5 protein in cultured skin fibroblasts from the patient and controls

TissueExpression: Cultured skin fibroblasts (CL:0002620) or "zone of skin" (UBERON:0000014)

ExpressionEvidence: Reduced CLN5 expression by 45% at the mRNA level (Figure 6) and by 50% at the protein level (Figure 7) indicates that one of the two alleles may be subject to nonsense mediated decay and likely absence of the corresponding protein product. This may confirm the prediction that the nonsense variant NM_006493.4(CLN5):c.418C>T (p.Gln140Ter) is likely subject to nonsense mediated decay.

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Genome-wide linkage analysis

CaseMethod2: Sanger sequencing of the candidate gene PDE6A

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

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

CAID: CA2573332091

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

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

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

CasePMIDs: N/A

PMID: 17110911

Gene: PDE6A

HGNC: 8785

Disease: retinitis pigmentosa 43

MONDO: MONDO:0013437

InheritancePattern: autosomal recessive

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

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

PMID: 23328348

Gene: GUCY2D

HGNC: 4689

Disease: Cone-rod dystrophy 6

MONDO: 0011143

InheritancePattern: Autosomal Dominant

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

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

ExperimentName: Transgenic zebrafish expressing human GUCY2D R838S

NonHumanModel: Danio rerio

GeneAlteration: A human GUCY2D transgene encoding either the wild-type protein or the the R838S substitution was placed under the control of the cone-specific gnat2 promoter and injected into zebrafish embryos, creating a transgenic model with cone-specific expression of the variant.

ModelPhenotype: HP:0410280 (Pediatric onset), HP:0000479 (Abnormal retinal morphology), HP:0030609 (Photoreceptor layer loss on macular OCT)

HumanPhenotype: HP:0000548 (Cone/cone-rod dystrophy), HP:0007663 (Reduced visual acuity), HP:0007994 (Peripheral visual field loss), HP:0000613 (Photophobia), HP:0011504 (Bull's eye maculopathy), HP:0030465 (Undetectable light-adapted electroretinogram), (Photoreceptor layer loss on macular OCT), HP:0410280 (Pediatric onset)

ModelEvidence: The model system approximately recapitulates the mode of inheritance (autosomal dominant) of the human disease state. Overexpression effects of the transgene were ruled out by comparison to the wild-type transgenic control, which did show some differences from the non-transgenic control. At the ocular level, larval optokinetic response (visual behavior) was normal. At the cellular/microscopic level, cone morphology was disrupted (Figures 2, 3, 4) and cone density was reduced (Figure 2), along with the thickness of the (rod) outer nuclear layer (Figure 5).

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

GroupName: Xin_2010_Group_1

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

GroupNotHPOs: N/A

NumberMales: Not mentioned

NumberFemales: Not mentioned

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

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

Race: Not mentioned

AgeRange: Between 4 and 17 years of age at onset

TotalNumber: 10

FamilyInfo: 0

NoFamily: 10

VariantCount: 10

NonVariant: 0

OtherVariant: 0

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

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

GroupMethod2: as mentioned

GroupGenotypingMethod: 47 original patients with an NCL phenotype but no variant in one of the 5 tested loci were subjected to CLN5 genotyping. PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. 10 patients were identified as harboring CLN5 variants. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

GroupAddInfo: N/A

PMID: 30588538

Gene: PROM1

HGNC: 9454

Disease: retinitis pigmentosa 41

MONDO: 0012796

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). The proportion of that incidence made up by the specific form caused by biallelic variants in PROM1 is not clear.

Penetrance: Known disease-causing alleles appear to be completely penetrant in the homozygous state, and for at least some heterozygous variants associated with other disease entities.

PMID: 19887631

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.

Case#: Chang_2009_Family_CHRO102_Proband_II:1, male, age and family origin not described

CasePresentingHPOs: HP:0011516 (Achromatopsia)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing of CNGA3, GNGB3, and GNAT2

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

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

Variant: The proband harbors the NM_006204.4(PDE6C):c.2368G>A (p.Glu790Lys) and NM_006204.4(PDE6C):c.1805A>T (p.His602Leu) variants in the compound heterozygous state.

ClinVar ID: 8769, 8772

gnomAD: The NM_006204.4(PDE6C):c.2368G>A (p.Glu790Lys) variant was not found in gnomAD v2.1.1. The NM_006204.4(PDE6C):c.1805A>T (p.His602Leu) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_006204.4(PDE6C):c.2368G>A (p.Glu790Lys) acts in part as an exonic splicing variant that has been expressed in COS7 cells and triggers 40% of transcripts to skip exon 21 and undergo frameshift (Figure S5C). The remaining transcripts encode a missense variant that has been expressed in Sf9 cells and subjected to an enzymatic assay showing approximately 40% loss of activity (Figure 5). NM_006204.4(PDE6C):c.1805A>T (p.His602Leu) is a missense variant that has been expressed in Sf9 cells and subjected to an enzymatic assay showing approximately 90% loss of activity (Figure 5).

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

CasePMIDs: N/A

PMID: 16754667

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 20

MONDO: 0013425

InheritancePattern: Autosomal Recessive

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

Penetrance: Fully penetrant, with onset typically in childhood

PMID: 19273593

Gene: ADAM9

HGNC: 216

Disease: cone-rod dystrophy 9

MONDO: MONDO:0013002

InheritancePattern: autosomal recessive

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

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

Case#: Perez-Roustit_2017_Proband, male, age 31 years, family ethnic origin not reported

CasePresentingHPOs: Nystagmus HP:0000639, Childhood onset HP:0011463, Reduced visual acuity HP:0007663, Presenile cataracts HP:0007819, Pigmentary retinopathy HP:0000580, Patchy atrophy of the retinal pigment epithelium HP:0007791, Undetectable light- and dark-adapted electroretinogram HP:0007688

CaseHPOFreeText: The proband received a diagnosis of Leber congenital amaurosis. His phenotype included increased retinal thickness and presence of hyper-reflective formations around the optic disc and periphery. Visual impairment was severe but did not evolve significantly during the first 30 years of age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was previously genotyped by screening for ABCA4 variants.

CaseMethod1: Sanger sequencing of the ABCA4 gene

CaseMethod2: Sanger sequencing of the KCNJ13 exons and intron-exon boundaries

CaseGenotypingMethod: The proband was previously genotyped by screening for ABCA4 variants, followed by Sanger sequencing of the KCNJ13 exons and intron-exon boundaries.

Variant: The individual is compound heterozygous with the maternal NM_002242.4(KCNJ13):c.314G>T (p.Ser105Ile) and paternal NM_002242.4(KCNJ13):c.655C>T (p.Gln219Ter) variants.

ClinVar: 978434, 978433

gnomAD: The NM_002242.4(KCNJ13):c.314G>T (p.Ser105Ile) variant was not found in gnomAD version 4.1.0. The NM_002242.4(KCNJ13):c.655C>T (p.Gln219Ter) variant is found in gnomAD version 4.1.0 at a frequency of 0.00002669 (2/74924) in the African / African-American population https://gnomad.broadinstitute.org/variant/2-232768619-G-A?dataset=gnomad_r4

VariantEvidence: NM_002242.4(KCNJ13):c.314G>T (p.Ser105Ile) is a missense variant that has no experimental evidence in this study. NM_002242.4(KCNJ13):c.655C>T (p.Gln219Ter) is a nonsense variant in exon 3 of 3 that is not predicted to trigger NMD but rather to truncate the C-terminal 39% of the protein product.

CaseAddInfo: The proband's family history is not known to include parental consanguinity or history of retinal disease.

CasePMIDs: N/A

CaseControlLabel: Aggregated *RPE65 variants in 187 apparently-unrelated Chinese probands from 16 provinces of China diagnosed with LCA by retina specialists and 200 ethnically matched apparently-unrelated healthy control individuals.

CaseCohortLabel: 187 apparently-unrelated Chinese probands from 16 provinces of China diagnosed with LCA by retina specialists

ControlCohortLabel: 200 ethnically matched apparently-unrelated healthy control individuals

CaseControlPhenotype: HP:0003593 (Infantile onset), HP:0030555 (Best corrected visual acuity 0.2 LogMAR)

CaseControlPhenotypeFreeText: The above phenotypes are noted only for the subset of LCA patients later found to have RPE65-related disease. Age at onset was within the first few months after birth. The best corrected visual acuity for individuals over 30 years old was less than 0.2, with few exceptions.

CaseControlNOTPhenotype: N/A

CaseDemographics: Country of origin for all case and control individuals is China, with recruitment area including all 16 provinces. Numbers of males and females, race, and age range are unspecified.

ControlDemographics: Control individuals are stated to be ethnically matched to the cases, but details are not provided.

CaseMethod: Previous testing for cases appears to have been limited to diagnosis of Leber's congenital amaurosis by a retina expert. Genotyping method was Sanger sequencing of PCR products from all 14 exons of RPE65. Targeted exome sequencing (194-gene panel) appears to have been performed for a subset of affected cases harboring RPE65 variants.

ControlMethod: Previous testing was not described. Genotyping method was Sanger sequencing of PCR products from all 14 exons of RPE65.

CasePower: 187 cases were genotyped, and 14 were found to harbor RPE65 variants (12 biallelic and 2 apparently monoallelic), with 11 cases predicted to harbor biallelic pathogenic RPE65 variants.

ControlPower: The number of control individuals who harbored a variant in RPE65 is not mentioned.

CaseAddInfo: Cases may have overlapped with other studies of Leber congenital amaurosis in Chinese cohorts (PMID: 29133760, PMID: 25356976, PMID: 26047050, PMID: 23661369, PMID: 22509104, PMID: 25383945, PMID: 21602930, PMID: 23661368, PMID: 28393863). The possibility of overlap is not addressed in the text.

ControlAddInfo: Overlap of the control cohort with other PMIDs is not reported.

CaseControlEvaluation: The study type is Aggregate analysis. The study used Sanger sequencing of the 14 exons of the RPE65 gene as the detection method. Cases counted were those found to harbor biallelic RPE65 variants that were predicted to be pathogenic at the protein level or demonstrated to have transcript-level impact through a minigene in vitro splicing assay.

CaseControlStats: Test statistic value, p-value, and confidence interval are not included in the report.

CaseControlBias: Matching was performed on the basis of ethnicity. While it is possible that age, gender, and other demographics were not as well-matched between cases and controls, the early onset of the disease makes these unlikely sources of bias. Because the process of matching is not described in detail, it is difficult to evaluate other sources of potential bias such as differences in local origin between cases and controls that might lead to false assumptions that certain individuals are unrelated.

CaseControlComments: N/A

PMID: 23776498

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: 18617546

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: 11827795

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: 33910932

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

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

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

Case#: Gu_1997_Patient_arRP341-II-1, female, age 3 months at onset, German ethnicity

CasePresentingHPOs: HP:0000505 (Visual impairment), HP:0003593 (Infantile onset), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram), HP:0030474 (Undetectable dark-adapted electroretinogram), HP:0007663 (Reduced visual acuity)

CaseHPOFreeText: The first detectable phenotype was observed at age 3 months, when no reactions to objects or faces were observed. Rod ERG was extinguished at age 8 months, while cone ERG flicker response was significantly decreased. Low visual acuity was found at age 3 years.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing was limited to clinical diagnosis of arRP.

CaseMethod1: PCR amplification and Sanger sequencing

CaseMethod2: N/A

CaseGenotypingMethod: RPE65 was subjected to PCR amplification and Sanger sequencing.

Variant: The patient is a compound heterozygote with the NM_000329.3(RPE65):c.11+5G>A (paternal) and NM_000329.3(RPE65):c.89dup (p.Thr31fs) (maternal) variants in trans.

ClinVar: 98825, 98898

gnomAD: The maximum allele frequency of the NM_000329.3(RPE65):c.11+5G>A variant is 0.0001626 (in the European non-Finnish population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68915573-C-T The NM_000329.3(RPE65):c.89dup (p.Thr31fs) variant was not found in gnomAD.

VariantEvidence: The paternal variant is located within intron 1 of the RPE65 transcript and affects part of the splice donor consensus sequence. SpliceAI calculates a delta score of 0.06 for loss of splice donor site. The maternal variant is located within exon 2 and encodes a frameshift predicted to truncate approximately 94% of the protein product.

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

CasePMIDs: N/A

FamilyLabel: Gu_1997_Family_PMK30

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

FamilyPresentingHPOFreeText: Onset of severe visual impairment between age 3 and age 7, progressing between the ages of 5 and 12. Vision was limited to counting fingers (at a distance of 1-3 meters) or seeing hand movements. Onset of severe

FamilyNotHPOs: N/A

CountryOrigin: India

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Previous testing consisted of linkage analysis using microsatellite repeat markers.

Family#Method1: PCR products from 2 affected and 1 control family members were screened by single-strand conformation polymorphism (SSCP) analysis. After discovery of a band shift for exon 10, those two patients were subjected to Sanger sequencing.

Family#Method2: A PCR-based assay was used to detect the variant of interest by introducing a BspMI restriction site into the wild-type PCR product.

Family#GenotypingMethod: Restriction enzyme-based screening of exon 10 PCR products

Affected: 4

Unaffected: 4

Segregations: 6 segregations were reported, with none inconsistent. The pedigree (Figure 1) shows consanguinity between the parents of each affected individual.

PublishedLOD: The LOD score was 3.57 at a 0.00 recombination fraction (for microsatellite repeat polymorphism D1S1665).

eLOD: 2.31

AddSegregationInfo: N/A

ProbandLabel: Gu_1997_Family_PMK30_Patient_V-5

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

ClinVar: 13117

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

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

FamilyPMIDs: N/A

Case#: Allikmets_1997_Proband_1, female, age described as between 55 and 70 years at time of diagnosis, family origin not reported

CasePresentingHPOs: HP:0000505 (Visual impairment), HP:0000608 (Macular degeneration)

CaseHPOFreeText: The proband has been diagnosed with age-related macular degeneration. She belongs to a cohort in which most AMD cases were diagnosed with dry rather than wet AMD, with a broad range of phenotypes including; drusen in the macular and/or peripheral retina and macular / RPE atrophy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and her family members have been genotyped by SSCP analysis of ABCA4 PCR products, followed by Sanger sequencing-based confirmation.

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of ABCA4

CaseGenotypingMethod: The proband and her family members have been genotyped by SSCP analysis of ABCA4 PCR products, followed by Sanger sequencing-based confirmation of the variant.

Variant: The proband harbors the NM_000350.3(ABCA4):c.6519_6529del (p.Lys2175fs) variant in the heterozygous state.

ClinVar ID: 99466

gnomAD: The variant was not found in gnomAD v4.1.0.

VariantEvidence: NM_000350.3(ABCA4):c.6519_6529del (p.Lys2175fs) is a frameshift variant in exon 48 of 50 that is predicted to trigger nonsense-mediated decay (or to truncate the C-terminal 4.4% of the protein product.

CaseAddInfo: The proband is the mother of a patient with a diagnosis of Stargardt disease. Her husband and brother-in-law have similarly been diagnosed with age-related macular degeneration between ages 55 and 70 years, but do not have an identified ABCA4 variant.

CasePMIDs: N/A

Case#: El-Haig_2014_Proband, female, age not specified, family origin reported to be Egyptian

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000548 (Cone/cone-rod dystrophy), HP:0007787 (Posterior subcapsular cataract), HP:0010923 (Anterior subcapsular cataract), HP:0000505 (Visual impairment), HP:0007703 (Abnormality of retinal pigmentation), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor)

CaseHPOFreeText: The proband and her affected family members have been diagnosed with cone-rod dystrophy, with the family showing an autosomal recessive mode of inheritance.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and her family were initially genotyped by IROme, which generates a hybridization-based DNA library of the 64 most frequently mutated genes in retinal dystrophy, then analyzes it by high-throughput sequencing.

CaseMethod1: Next-generation sequencing panel

CaseMethod2: Sanger sequencing of ADAM9 exon 14 and flanking exon-intron junctions

CaseGenotypingMethod: The proband and her family were initially genotyped by IROme, which generates a hybridization-based DNA library of the 64 most frequently mutated genes in retinal dystrophy, then analyzes it by high-throughput sequencing. Sanger sequencing of ADAM9 exon 14 and flanking exon-intron junctions was then performed.

Variant: The proband harbors the NM_003816.3(ADAM9):c.1396-2A>G variant in the homozygous state.

ClinVar: 189795

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

VariantEvidence: NM_003816.3(ADAM9):c.1396-2A>G is a variant disrupting a canonical splice site in intron 13, which is predicted but not confirmed to disrupt mRNA splicing.

CaseAddInfo: The proband is from a consanguineous family and has two affected sons who are also homozygous for the variant, as well as five unaffected heterozygous family members.

CasePMIDs: N/A

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

SRF1186

Case#: Parry_2009_Family_MOL0172_patient_IV:3, male, age not specified, family origin reported to be Tunisian Jewish

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.490C>T (p.Arg164Ter) variant in the homozygous state.

ClinVar: 6878

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

VariantEvidence: NM_003816.3(ADAM9):c.490C>T (p.Arg164Ter) is a nonsense variant in exon 6 of 21, and is therefore predicted to result in nonsense-mediated decay.

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

CasePMIDs: N/A

PMID: 24419317

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.

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

PMID: 30718709

Gene: PDE6A

HGNC: 8785

Disease: retinitis pigmentosa 43

MONDO: MONDO:0013437

InheritancePattern: autosomal recessive

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

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

Case#: Jespersgaard_2019_Patient_168, gender and age not specified, origin likely to be Danish based on cohort

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel

CaseMethod2: N/A

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

Variant: The proband harbors the NM_000440.3(PDE6A):c.1407+1G>A variant in the homozygous state.

ClinVar: 636053

gnomAD: The NM_000440.3(PDE6A):c.1407+1G>A variant is found in gnomAD v2.1.1 at a frequency of 0.0003267 (1/30606 with no homozygotes) in the South Asian population https://gnomad.broadinstitute.org/variant/5-149277925-C-T

VariantEvidence: The NM_000440.3(PDE6A):c.1407+1G>A variant disrupts a canonical splice site in intron 10, but does not have experimental confirmation of exon skipping or frameshift.

CaseAddInfo: N/A

CasePMIDs: N/A

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Whole exome sequencing

CaseMethod2: Confirmation by Sanger sequencing

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

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

ClinVar: 812328

gnomAD: The variant was not found in gnomAD.

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

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

CasePMIDs: N/A

PMID: 32039639

Gene: CTNNB1

HGNC: 2514

Disease: severe intellectual disability-progressive spastic diplegia syndrome

MONDO: 0014035

InheritancePattern: autosomal dominant

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

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

Selection B- Gene function is consistent with phenotype.

GOterm: GO:0030991 (intraciliary transport particle A)

FunctionalEvidence: Mass spectrometry analysis of IFT-A complex components co-purifying with the TULP3 protein identified the IFT140 protein along with several other known components such as WDR19, IFT122, THM1, and WDR35 (Figure 1C). These other IFT-A components were also confirmed by mass spectrometry to co-purify with IFT140 itself (Figure 1C).

FunctionalHPO: Absence of primary cilia in a high number of cells from the affected patients (shown using acetylated alpha-tubulin staining of cultured fibroblasts)

PhenotypeEvidence: Primary cilia from the affected patients are known to be absent from a high proportion of cells in the affected individuals, while the gene product functions in a complex known to participate in retrograde ciliary transport (Figure 1A, 1C). This trafficking process is known to be mediated by the IFT-A complex and is critical to the assembly and maintenance of cilia.

Case#: Bowne_2011_Family_TCD-H_Patient_01, male, unspecified age, family origin in Ireland

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient was provisionally diagnosed with choroideremia prior to genotyping that excluded the presence of a variant in the CHM locus.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Candidate gene sequencing of the CHM locus to exclude the initial diagnosis of choroideremia

CaseMethod1: Two-point linkage analysis of the RPE65 locus, as well as haplotype analysis using STR genotypes surrounding the variant of interest

CaseMethod2: Candidate gene sequencing

CaseGenotypingMethod: Sanger sequencing of the RPE65 locus

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

ClinVar: 750796

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

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

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Shin_2015_Proband, male, age 26 years at time of report, national origin reported as Korean

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

CaseHPOFreeText: The patient has been diagnosed with Bardet-Biedl syndrome and has poor corticomedullary differentiation in the kidneys and optic disc atrophy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of Sanger sequencing of the BBS1, BBS2, BBS3, BBS4, BBS5, BBS6, BBS8, BBS9, BBS10, BBS11, BBS12, BBS13, and BBS14 genes.

CaseMethod1: Sanger sequencing of the BBS1, BBS2, BBS3, BBS4, BBS5, BBS6, BBS8, BBS9, BBS10, BBS11, BBS12, BBS13, and BBS14 genes

CaseMethod2: Sanger sequencing of the BBS7 locus

CaseGenotypingMethod: Genotyping was performed using Sanger sequencing of the BBS1, BBS2, BBS3, BBS4, BBS5, BBS6, BBS7, BBS8, BBS9, BBS10, BBS11, BBS12, BBS13, and BBS14 genes.

Variant: The patient harbors the NM_018190.4:c.103-1G>A and NM_018190.4:c.728G>A (p.Cys243Tyr) variants in the compound heterozygous state.

ClinVar ID: 166738

CAID: CA358045281

gnomAD: The NM_018190.4:c.103-1G>A variant was not found in gnomAD v2.1.1. The NM_018190.4:c.728G>A (p.Cys243Tyr) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.0005515 (11/19944) in the East Asian population, with no homozygotes https://gnomad.broadinstitute.org/variant/4-122774232-C-T

VariantEvidence: NM_018190.4:c.103-1G>A is a canonical splice site variant in intron 2 adjacent to the boundary with exon 3 and does not have functional evidence of an impact on the protein product. NM_018190.4:c.728G>A (p.Cys243Tyr) is a missense variant in exon 8 that does not have functional evidence of an impact on the protein product, but has been previously reported in the homozygous state in a patient affected with retinitis pigmentosa (PMID: 23847139).

CaseAddInfo: Consanguinity is not present in the proband's family. He has a similarly affected brother who shares the same compound heterozygous genotype, and unaffected parents and sibling who each carry one BBS7 variant.

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

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

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

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

ClinVar: 191155

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

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

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

CasePMIDs: N/A

ExperimentName: Mouse ciliated cell model of Ift140 loss-of-function

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

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

GeneAlteration: The cell line was subjected to CRISPR-based knockout of endogenous IFT140.

CellPhenotype: Ift140 knockout cells exhibited a complete inability to form cilia relative to the control rescued by overexpression of wild-type Ift140 (Figure 3b).

CellEvidence: The defect in ciliary formation induced by Ift140 knockout (Figure 3b) recapitulates one of the cellular features of human patients harboring IFT140 variants (absence of cilia from a high proportion of fibroblasts). This also matches the Chlamydomonas model of IFT140 loss described in PMID: 28207750, albeit with greater severity.

CellVariant: CRISPR-based knockout was performed in this study to mimic IFT140 loss of function, while the human IFT140 variants were tested in the related rescue experiment instead.

Case#: Bernal_2008_Proband_B-30, female, age 30 years at time of report, national origin from Spain

CasePresentingHPOs: Nyctalopia HP:0000662, Childhood onset HP:0011463, Reduced visual acuity HP:0007663, Constriction of peripheral visual field HP:0001133

CaseHPOFreeText: The proband has a diagnosis of retinitis pigmentosa, and had hypopigmented clumped lesions in the posterior pole of 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.119-2A>C variant in the homozygous state.

ClinVarID: 191059

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

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

CaseAddInfo: The proband has an affected sibling who shares the same homozygous genotype.

CasePMIDs: N/A

PMID: 17251447

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

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

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

PMID: 30688845

Gene: IMPG1

HGNC: 6055

Disease: vitelliform macular dystrophy 4

MONDO: 0014508

InheritancePattern: semi-dominant

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

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

Case#: Thiadens_2009_Family_D_Proband_DII-1, female, age 12 years at onset and 37 years at the time of report, sites of treatment listed as the Netherlands, Belgium, U.K., or Canada

CasePresentingHPOs: HP:0030534 (Abnormal best corrected visual acuity test), HP:0000613 (Photophobia, described as severe), HP:0000639 (Nystagmus), HP:0031624 (Moderate myopia), HP:0000551 (Color vision defect, described as severe), HP:0030825 (Absent foveal reflex), HP:0030465 (Undetectable light-adapted electroretinogram)

CaseHPOFreeText: The proband and affected family member were previously diagnosed with complete achromatopsia. The proband had onset by age 12 years.

CaseNotHPOs: HP:0007769 (Peripheral retinal degeneration)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in this family appears to have been limited to phenotype analysis.

CaseMethod1: screening of the 22 exons and flanking regions of PDE6C (candidate gene) using Sanger sequencing

CaseMethod2: N/A

CaseGenotypingMethod: Affected and unaffected family members were subjected to Sanger sequencing-based screening of the 22 exons and flanking regions of PDE6C.

Variant: The proband harbors the NM_006204.4(PDE6C):c.633G>C (p.Glu211Asp) and NM_006204.4(PDE6C):c.1363A>G (p.Met455Val) variants in the compound heterozygous state.

ClinVar ID: 8768, 8767

gnomAD: Neither variant was found in gnomAD v2.1.1.

VariantEvidence: NM_006204.4(PDE6C):c.1363A>G (p.Met455Val) is a missense variant that does not have experimental evidence of a functional effect on the protein product. NM_006204.4(PDE6C):c.633G>C (p.Glu211Asp) is not a missense variant but rather a substitution of the last base pair of exon 2 that is predicted to disrupt the splice donor site.

CaseAddInfo: The patient's parents are apparently unaffected carriers. Her similarly affected sibling shares the same compound heterozygous genotype.

CasePMIDs: N/A

Reduced amplitude of dark-adapted bright flash electroretinogram a-wave HP:0030483 (Figure 4), Reduced OCT-measured macular thickness HP:0030607 (Figure 2), immunoblot analysis showing reduced L185P in retinas, indicating instability or reduced transport to the outer segment (Figure 5b).

Case#: Weisschuh_2020_Patient_BVMD_75, male, age 61 years at diagnosis, age 66 years at report, national origin reported as German

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of next generation sequencing-based RET.6 panel.

CaseMethod1: next generation sequencing-based RET.6 panel

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was performed using a next-generation sequencing-based RET.6 panel.

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

ClinVar: 813048

gnomAD: The NM_001563.4(IMPG1):c.807+1G>C variant was not found in gnomAD v2.1.1.

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: Segregation confirmation in family members is not available. The patient has a genotype that has been reported elsewhere in an apparently separate proband (PMID: 23993198, apparently of Italian national origin).

CasePMIDs: N/A

ExperimentName: Functional characterization of patient-derived hiPSC-RPE cells

PatientCell: CL:0002586, or retinal pigment epithelial cell (retinal pigmented epithelium generated from patient-derived induced pluripotent stem cells, or hiPSC-RPE)

GeneFunction: GO:0008191 (metalloendopeptidase inhibitor activity), GO:0051045 (negative regulation of membrane protein ectodomain proteolysis), GO:0016525 (negative regulation of angiogenesis)

GeneAlteration:** Patient cells were heterozygous carriers of the NM_000362.5(TIMP3):c.610A>T p.Ser204Cys variant, or unaffected controls that were homozygous for the non-variant allele.

FunctionalEvidence: hiPSC-RPE cells from SFD patients exhibit altered function relative to equivalent cells from unaffected individuals. They secrete a decreased quantity of TIMP3 (Figure 4C), indicating accumulation and retention of TIMP3 either within the cells or in the associated extracellular matrix. Finally, they express abnormal proteomic profiles with elevated levels of the known TIMP3 binding partner EFEMP1 and the known drusen component apolipoprotein E (Figure 5). The epithelial layer formed by these patient-derived cells exhibits reduced transepithelial electrical resistance (Figure 2C). Other known functions like metalloproteinase inhibition are retained by the variant-harboring cells (Figure 4D). These findings are consistent with a gain-of-function mechanism.

FAVariants: This experiment studied patient cells harboring the NM_000362.5(TIMP3):c.610A>T p.Ser204Cys variant (ClinVarID 12676).

PMID: 7894485

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: 12524598

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

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

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

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

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

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

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

PMID: 16252235

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

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

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

Case#: Suspitsin_2015_Proband_II.4, male, age 7 years at time of report, national origin reported as Russian

CasePresentingHPOs: HP:0004324 (Increased body weight), HP:0012743 (Abdominal obesity), HP:0000510 (Rod-cone dystrophy), HP:0100259 (Postaxial polydactyly), HP:0011220 (Prominent forehead), HP:0005280 (Depressed nasal bridge), HP:0000054 (Micropenis), HP:0001256 (Intellectual disability, mild), HP:5200120 (Abnormality in emotional social interactions)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of exome sequencing, focused on the BBS1-BBS19 loci.

CaseMethod1: exome sequencing

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping consisted of exome sequencing, focused on the BBS1-BBS19 loci.

Variant: The patient harbors the NM_176824.3(BBS7):c.1967_1968delinsC (p.Leu656fs) variant in the homozygous state.

ClinVar ID: 162088

gnomAD: The NM_176824.3(BBS7):c.1967_1968delinsC (p.Leu656fs) variant was not found in gnomAD v2.1.1. However, the authors note that the healthy blood donors from the Russian population do carry the allele in the heterozygous state at a low frequency (0.07%).

VariantEvidence: NM_176824.3(BBS7):c.1967_1968delinsC (p.Leu656fs) is an out-of-frame indel in exon 18 of 18 and is not predicted to trigger nonsense-mediated decay but rather to truncate the C-terminal 8% of the protein product.

CaseAddInfo: The proband is a member of a non-consanguineous family, and has two unaffected carrier parents, an unaffected carrier sibling, and a similarly affected sister sharing the same homozygous genotype.

CasePMIDs: N/A

PMID: 28575650

Gene: CTNNB1

HGNC: 2514

Disease: severe intellectual disability-progressive spastic diplegia syndrome

MONDO: 0014035

InheritancePattern: autosomal dominant

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

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

PMID: 8728699

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#: Nichols_1993_Proband, female, age and family origin not reported

CasePresentingHPOs: Subretinal deposits HP:0031528

CaseHPOFreeText: The proband has been diagnosed with butterfly-shaped pigment dystrophy of the fovea. All affected family members including the proband exhibited perifoveal yellow pigment deposits at the level of the RPE.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in this family appears to have been limited to the PRPH2 locus and did not include other candidates genes.

CaseMethod1: single-strand conformational polymorphism (SSCP) analysis of PCR products from the 3 exons of PRPH2

CaseMethod2: Sanger sequencing of PRPH2

CaseGenotypingMethod: Previous testing in this family appears to have been limited to the PRPH2 locus and did not include other candidates genes. Genotyping was performed by single-strand conformational polymorphism (SSCP) analysis of PCR products from the 3 exons of PRPH2, followed by Sanger sequencing of PRPH2 to identify the variant.

Variant: The proband harbors the NM_000322.5(PRPH2):c.897_898del (p.Ser301fs) variant in the heterozygous state.

ClinVar ID: 13171

gnomAD: The NM_000322.5(PRPH2):c.897_898del (p.Ser301fs) variant was not found in gnomAD v4.0.0.

VariantEvidence: NM_000322.5(PRPH2):c.897_898del (p.Ser301fs) is a frameshift variant in exon 3 of 3 that is predicted not to trigger nonsense-mediated decay but rather to truncate the C-terminal 14% of the protein product.

CaseAddInfo: The proband has two affected sisters and an affected father who similarly carry the variant, as well as 6 unaffected family members who are negative for the variant.

CasePMIDs: N/A

PMID: 23469166

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

ExperimentName: Morpholino-based disruption of Impg1 in medaka fish

NonHumanModel: Oryzias latipes

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

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

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

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

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

PMID: 15824229

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#: Méjécase_2020_Family_6_Proband_6-1, sex not specified, age 8 years, family national origin described as from the United Arab Emirates

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband received a diagnosis of severe early onset retinal dystrophy. The fundus appearance was described as consistent with KCNJ13-retinopathy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was previously genotyped by a next-generation sequencing panel.

CaseMethod1: next-generation sequencing panel

CaseMethod2: Sanger sequencing of KCNJ13

CaseGenotypingMethod: The proband was previously genotyped by a next-generation sequencing panel, followed by Sanger sequencing-based confirmation.

Variant: The individual harbors the NM_002242.4(KCNJ13):c.431T>C (p.Leu144Pro) variant in the homozygous state.

ClinVar: 916717

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.00001667 (1 / 59998) in the African / African-American population https://gnomad.broadinstitute.org/variant/chr2-232770932-A-G?dataset=gnomad_r4

VariantEvidence: NM_002242.4(KCNJ13):c.431T>C (p.Leu144Pro) is a missense variant that has no experimental evidence in this study

CaseAddInfo: The proband's family history includes a similarly affected 4-year-old sibling with the same homozygous genotype.

CasePMIDs: N/A

PMID: 24801621

Gene: OPN1LW

HGNC: 9936

Disease: protan color blindness

MONDO: 0010565

InheritancePattern: X-linked

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

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

PMID: 27718025

GeneName: GNAT2

HGNC: 4394

Disease: achromatopsia 4

MonDO ID: MONDO_0013465

Inheritance: autosomal recessive

PMID: 34985506

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: Jacobson_1995_Family_1_Patient_III-5, male, country of origin United States (PMID:8981947), onset in 4th or early 5th decade of life

DiseaseAssertion: Sorsby's fundus dystrophy

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

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

CaseHPOFreeText: Onset in the 4th or early 5th decade of life with drusen appearing first and progression to macular scarring (secondary to subretinal hemorrhage) and degeneration.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

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

GenotypingMethod: PCR amplification of exon 5, followed by enzyme digestion with the Bbv1 restriction endonuclease.

PreviouslyPublished: N/A

SupplementalData: N/A

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

CAID: CA411540415

gnomAD: Variant is absent from gnomAD.

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

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: Single strand conformational polymorphism analysis

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

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

ClinVar: 98607

gnomAD: The variant is absent from gnomAD version 2.1.1.

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

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 7581387, PMID: 8641699

PMID: 10396622

Gene: ABCA4

HGNC: 34

Disease: age related macular degeneration 2

MONDO: 0007932

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of age-related macular degeneration is estimated to be 9.9-19.5% (early-stage) or 1.1-3.9% (late-stage) among all people over age 50 years (PMID: 31712255).

Penetrance: The penetrance of proposed disease-causing alleles is not clear but is expected to be incomplete and age-dependent.

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

ExperimentName: Lrp5 expression in mouse embryonic osteoblasts coincides with bone formation / ossification.

TissueExpression: UBERON:0003129 (skull)

ExpressionEvidence: In situ hybridization first detects Lrp5 expression in the mouse clavicle at embryonic day 14, when membranous ossification is occurring (Fig. 3A) and when other markers of skeletal differentiation are present. Lrp5 is also seen at embryonic day 16.5 in osteoblasts along the endosteal surface of the developing humerus, but not in growth plates (Fig. 3B). Finally, osteoblasts in the developing calvaria (skull) exhibit Lrp5 expression as well (Fig. 3C). All three observations support a role for LRP5 in bone formation, which is consistent with the phenotype of osteoporosis in patients with biallelic loss-of-function.

PMID: 28566226

Gene: RPGR

HGNC: 10295

Disease: RPGR-related retinopathy

MONDO: MONDO:0100437

InheritancePattern: X-linked

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

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

PMID: 9614228

Gene: RBP3

HGNC: 9921

Disease: retinitis pigmentosa 66

MONDO: 0014093

InheritancePattern: autosomal recessive

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

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

FamilyLabel: Lin_2006_Family_1

Family#PresentingHPOs: HP:0011506 (Choroidal neovascularization), HP:0011510 (Drusen), HP:0007722 (Retinal pigment epithelial atrophy), HP:0000662 (Nyctalopia), HP:0007850 (Retinal vascular proliferation)

FamilyHPOFreeText: Disease onset was between the fifth and seventh decades of life. Mild nyctalopia preceded choroidal neovascularization by one or more decades in most individuals. Drusen, RPE atrophy, thickening of Bruch's membrane, and blockage of normal central choroidal fluorescence were also early stage disease phenotypes that preceded choroidal neovascularization. Choroidal neovascularization was bilateral in 4 out of 7 affected family members.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Family reported to have Eastern European Jewish ancestry.

Family#PreviousTesting: Complete ophthalmological exam to define clinical features of affected family members.

Family#GenotypingMethod: Bidirectional Sanger sequencing of PCR products from exons 1 through 5, for 7 affected and 2 unaffected family members.

Affected: 7

Unaffected: 1

Segregations: 13

PublishedLOD: N/A

eLOD: 3.9

AddSegregationInfo: N/A

ProbandLabel: Lin_2006_Family_1_patient_IV-8

Variant: NM_000362.5(TIMP3):c.542A>G, p.His181Arg is a missense variant predicted to replace a conserved histidine residue in exon 5 with arginine (conservative substitution).

CAID: CA411540357

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

Patient G000986 has retinitis pigmentosa and is a compound heterozygote harboring two IMPG2 variants ().

Selection B - Gene function is consistent with phenotype.

GOterm: GO:0052885 (all-trans-retinyl-ester hydrolase, 11-cis retinol forming activity)

FunctionalEvidence: Exogenous co-expression of RPE65 and the LRAT enzyme in QBI-293A or COS-1 cells provides these cells with the enzymatic ability to generate 11-cis retinol from all-trans retinyl ester, identifying RPE65 as the human isomerohydrolase enzyme (Figures 4B-4F).

FunctionalHPO: HP:0007688 (Undetectable light- and dark-adapted electroretinogram), HP:0000529 (Progressive visual loss), HP:0000618 (Blindness)

PhenotypeEvidence: Maintenance of vision is dependent upon the visual retinoid cycle to enzymatically regenerate 11-cis retinal following the light-induced isomerization of this pigment to all-trans retinal. Isomerohydrolase is an enzymatic activity known to be responsible for this conversion and known to localize to the retinal pigment epithelium, but not previously mapped to a human gene prior to this study. The present paper identifies the RPE65 protein as the human isomerohydrolase enzyme, linking its biallelic loss to congenital blindness (Figures 4B-4F).

Case#: Fishman_1998_Family_1_Patient_IV-6, male, age 18 at time of study, 6 years old at time of first examination, family origin Scottish and Irish, race reported as white

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy), HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0007994 (Peripheral visual field loss), HP:0000613 (Photophobia), HP:0030534 (Abnormal best corrected visual acuity test), HP:0000577 (Exotropia), HP:0008043 (Retinal arteriolar constriction), HP:0007737 (Bone spicule pigmentation of the retina), HP:0001105 (Retinal atrophy), HP:0000550 (Undetectable electroretinogram), HP:0000573 (Retinal hemorrhage)

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, with the family exhibiting X-linked pattern of inheritance. Disease was reported to be relatively severe in this family.

CaseNotHPOs: HP:0012632 (Abnormal intraocular pressure), HP:0007957 (Corneal opacity), HP:0012795 (Abnormality of the optic disc)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was not subjected to previous genetic testing outside of the RPGR locus.

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

CaseMethod2: N/A

CaseGenotypingMethod: The proband and his family members were subjected to Sanger sequencing of the PCR-amplified exons from the RPGR locus.

Variant: The proband harbors the NM_001034853.2(RPGR):c.179G>T (p.Gly60Val) variant in the hemizygous state.

ClinVar: 9902

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

VariantEvidence: NM_001034853.2(RPGR):c.179G>T (p.Gly60Val) is a missense variant in exon 3 that has not been functionally characterized to confirm an impact on the gene product. It has been observed in multiple apparently unrelated families in this study (PMID: 9855162) and in one other study by the same group (PMID: 9399904). It may be a founder variant present within the population of the U.K.

CaseAddInfo: The proband is a member of Family 1, shown in Figure 1 from this study. Four other genotype-positive affected males are present in his extended family, as well as carrier females affected with patchy retinopathy (but no tapetal reflex).

CasePMIDs: N/A

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

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0011003 (High myopia), HP:0007663 (Reduced visual acuity), HP:0007787 (Posterior subcapsular cataract), HP:0100018 (Nuclear cataract), HP:0030856 (Posterior staphyloma), HP:0007401 (Macular atrophy), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007722 (Retinal pigment epithelial atrophy), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007688 (Undetectable light- and dark-adapted electroretinogram)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

Variant: The affected family members harbor the NM_016247.4(IMPG2):c.635C>G (p.Ser212Ter) variant in the homozygous state.

ClinVar: 3546

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

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

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

CasePMIDs: PMID: 20673862

PMID: 37091798

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#:Table II, MPS-1, Enzyme activity=1.06*

DiseaseAssertion: MPS1

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: 1.06 umol/hr/L blood, newborn blood spot

CaseUrineGAGs:

CaseERT:

CaseBMT:

Variant1:c.355G>T (p.Asp119Tyr)

Variant1ClinVarID: 2432701

Variant1CAID: CA2801882

Variant2: c.250G>A (p.Gly84Ser)

Variant2ClinVarID: 726495

Variant2CAID: CA2801152

AdditionalVariants:

ParentalGenotype:

PreviouslyPublished

PMID: 40673043

Gene: VWF

HGNCID: HGNC:12726

PMID: 23690449

Gene: VWF

HGNC: 12726

Disease: von Willebrand Disease Type 2N

MONDO: 0015631

InheritancePattern: Autosomal Recessive

Prevalence: Various sources (PMID: 28847738, PMID:19809303, PMID:29115006) can be combined to estimate the prevalence of VWD Type 2N between 1:15,000 and 1:80,000.

Penetrance: VWD type 2 is fully penetrant / nearly fully penetrant for most pathogenic variants.

ExperimentName: Transient expression of VWD type 2N variants in 293T cells

NonPatientCell: human embryonic kidney 293T cells (EFO:0001082)

GeneFunction: GO:0005515 (protein binding, specifically to Factor VIII)

GeneAlteration: A mutation encoding p.His817Gln was introduced into a construct for exogenous expression of the VWF protein.

FunctionalEvidence: The variant protein exhibited a mild defect in FVIII binding relative to the wild-type (less severe than other VWD type 2N variants) (Figure 1C). Because of the defect in FVIII interaction, the variant also exhibits mildly reduced cleavage by ADAMTS13 (Figures 1F, 1G, and 1H).

FAVariants: A construct equivalent to the c.2451T>A (p.His817Gln) variant was used (ClinVar:100224).

PMID: 25185554

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2M

MONDO: 0015630

InheritancePattern: Autosomal Dominant

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

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

PMID: 29868607

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2M

MONDO: 0015630

InheritancePattern: Autosomal Dominant

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

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

PMID: 26345337

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2B

MONDO: 0015629

InheritancePattern: Autosomal Dominant

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

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