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

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

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

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

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: Confirmation by Sanger sequencing of exon 15.

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

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

ClinVar: 617917

gnomAD: The variant was not found in gnomAD.

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

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

CasePMIDs: PMID: 9733038, PMID: 8733141

PMID: 22695961

Gene: GUCY2D

HGNC: 4689

Disease: Cone-rod dystrophy 6

MONDO: 0011143

InheritancePattern: Autosomal Dominant

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

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

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel / WES / WGS

CaseMethod2: Sanger sequencing of RBP3

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

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

ClinVar ID: 964958

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

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

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

CasePMIDs: N/A

PMID: 37806543

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.

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

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

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

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

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: Sanger sequencing of the BBS7 locus.

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

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

CAID: CA2580617740, CA358058685

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

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

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

CasePMIDs: N/A

PMID: 9006347

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

PMID: 15504042

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.

PMID: 29659842

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 87 with choroidal involvement

MONDO: 0032873

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of Retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.

Penetrance: Incomplete penetrance, estimated at 80%

FamilyLabel: Meunier_2016_Family_2

Family#PresentingHPOs: HP:0000662 (Nyctalopia), HP:0030506 (Yellow/white lesions of the retina), HP:0011510 (Drusen), HP:0007663 (Reduced visual acuity), HP:0000529 (Progressive visual loss), HP:0011506 (Choroidal neovascularization), HP:0007401 (Macular atrophy), HP:0007703 (Abnormality of retinal pigmentation), Bronchial wall thickening HP:0033542

FamilyHPOFreeText: Both eye and lung disease presented at later ages within members of this family. Eye disease onset occurred in the fifth decade of life with nyctalopia as the first presenting phenotype, and drusen / yellow lesions detectable at the posterior pole and in the peripheral retina. Choroidal neovascularization occurred during the 5th and 6th decades of life and led to progressive loss of vision in both eyes. Macular atrophy and retinal pigment abnormalities were also late presenting phenotypes. In addition to bronchial wall thickening, mild cylindrical bronchiectasis and asthma were each observed in one affected family member. Pulmonary symptoms were late in onset and only detected by CT imaging.

FamilyNotHPOs: HP:0025223 (Triggered by smoking), HP:0002097 (Emphysema),

FamilyNotHPOFreeText: No history of smoking

CountryOrigin: Family origin was not reported.

Family#PreviousTesting: Clinical exams to detail features of affected family members.

Family#GenotypingMethod: Sanger sequencing of PCR products from TIMP3 exons 1 through 5.

Affected: 4

Unaffected: 3

Segregations: 3

**PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: Insufficient number of segregations to estimate LOD score.

ProbandLabel: Meunier_2016_Family_2_patient_III-2

Variant: NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys) is a missense variant predicted to introduce a new cysteine-encoding codon into exon 1. Interestingly, it differs from most other published missense variants in that it affects a codon within exon 1 rather than exon 5.

ClinVar: 843268

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: Family has not been previously described but the same variant has been published in PMID:23023527, PMID:26493035, and PMID:30668888 (without reporting pulmonary symptoms in either study).

Case#: Zito_2003_Family_4462_Patient_IV.3, male, age 25 years. ethnicity not specified

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000662 (Nyctalopia), HP:0001133 (Constriction of peripheral visual field), HP:0000618 (Blindness), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0410018 (Recurrent ear infections), HP:0000365 (Hearing impairment), HP:0011108 (Recurrent sinusitis), HP:0002783 (Recurrent lower respiratory tract infections), HP:0002837 (Recurrent bronchitis), HP:0100582 (Nasal polyposis), HP:0000083 (Renal insufficiency)

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, with the family exhibiting an X-linked pattern of inheritance.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and family members were subjected to haplotype analysis using microsatellite markers on the X chromosome.

CaseMethod1: Haplotype analysis

CaseMethod2: Sanger sequencing of PCR products from the RP2, RPGR, and TCTE1L loci

CaseGenotypingMethod: The proband and family members were subjected to haplotype analysis using microsatellite markers on the X chromosome, followed by Sanger sequencing of PCR products from the RP2, RPGR, and TCTE1L loci.

Variant: The proband harbors the NM_001034853.2(RPGR):c.789_790del (p.Thr265fs) variant in the hemizygous state.

ClinVar: 9915

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

VariantEvidence: NM_001034853.2(RPGR):c.789_790del (p.Thr265fs) is a frameshift variant in exon 8 of exon 15 that is predicted to trigger nonsense-mediated decay or at least to disrupt ~68% of the C-terminus of the protein product.

CaseAddInfo: The proband is a member of Family 4462 (shown in Figure 1), which includes two other affected genotype-positive males and two confirmed carrier females described as having myopia and sparse peripheral intra-retinal pigmentation.

CasePMIDs: N/A

ExperimentName: Continued studies of mouse model with hemizygous disruption of the GPR143 ortholog Oa1

NonHumanModel: Mus musculus

GeneAlteration: A hemizygous mouse model of Oa1 knockout was previously generated by replacement of exon 1 (including the start codon) with a cassette to facilitate selection (PMID: 11092754).

ModelPhenotype: HP:0003593 (Infantile onset), HP:0005592 (Giant melanosomes in melanocytes), severely reduced microtubule-based motility in melanosomes

HumanPhenotype: HP:0000639 (Nystagmus), HP:0003593 (Infantile onset), HP:0007663 (Reduced visual acuity), HP:0001361 (Nystagmus-induced head nodding), HP:0000646 (Amblyopia), HP:0000483 (Astigmatism), HP:0000613 (Photophobia), normally pigmented skin and hair, HP:0005592 (Giant melanosomes in melanocytes), HP:0007750 (Hypoplasia of the fovea), HP:0007894 (Hypopigmentation of the fundus), HP:0025551 (Optic nerve misrouting)

ModelEvidence: The mice match the human patients in that they exhibit congenital onset of cytological abnormalities (PMID: 16303920), These were previously shown in the RPE and are here shown in the melanocytes as well (Figure 3). Most importantly, this study shows a defect in microtubule-based melanosome motility (Figure 7), indicating an underlying mechanism for the disease.

ModelVariant: This model features disruption of Oa1 by knockout, but does not harbor a mutation equivalent to a variant from a human patient.

Does model have relevance to bone density or retinal function?

PMID: 10676808

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.

PMID: 15231740

Gene: BBS7

HGNC: 18758

Disease: Bardet-Biedl syndrome 7

MONDO: 0014435

InheritancePattern: autosomal recessive

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

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

Case#: P8-CH, F, Age or Report: 36 y.o. Age of Onset: Teens, Ethnicity: Switzerland.

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0030329 (Retinal thinning/reduced retinal thickness), HP:0005101 (High-frequency hearing impairment)

CaseHPOFreeText: This proband started experiencing a decrease in visual acuity since her teens, followed by night blindness, and was referred for an ophthalmological assessment at the age of 16 years. She was from a non-consanguineous family, however both parents came from the same village (Fig. 1f).

At the first visit, her BCVA was 0.3 D in both eyes and the scotopic ERG responses were severely reduced, while the 30-Hz Flicker had reduced amplitude. At her last visit, aged 38 years, her BCVA was 0.1 D in both eyes, and the GVF was reduced to 30° bilaterally. FAF imaging showed several areas of patchy hypoautofluroescence at the posterior pole, which increased over time. The OCT scans at the last visit showed reduced retinal thickness with a severely altered layer of RPE and an absent ellipsoid layer at the posterior pole (Fig. 2f, Table 2). She never complained of hearing problems, however, the audiogram perfomed when she was 36 years old showed a reduced hearing threshold at higher frequencies (between 2000 and 4000 Hz) to 35 dB in the right ear and to 20 dB in the left side (Fig. 3, Table 2).

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_021831.6:c.908G>A (p.Arg303His).

ClinVar: 1044022.

CAID: CA1567753.

gnomAD: Frequency: 0.00001995. Link: https://gnomad.broadinstitute.org/variant/chr2-27055253-G-A?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: No other family member had vision problems, however her younger sister (II.3) had severe hearing impairment (Fig. 1f). The genetic testing of the proband revealed a homozygous missense variant c.908G>A, p.(Arg303His) in the AGBL5 gene (Table 1, Fig. 1f). The sister who presented isolated severe hearing loss was heterozygous for the AGBL5 variant but was found to be compound heterozygous for two variants (c.35del and c.2229T>C) in the GJB2 gene, explaining her hearing impairment (Fig. 1f). The proband did not carry any of the GJB2 variants.

CasePMIDs: N/A.

PMID: 25277229

GeneName: GNAT2

HGNC: 4394

Disease: achromatopsia 4

MonDO ID: MONDO_0013465

Inheritance: autosomal recessive

Case#: Morimura_1998_Family_0748_Patient_II-1, female, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

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

Variant: The proband is a homozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.643+2T>A variant.

ClinVar: 940479 (homozygous)

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

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

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

CasePMIDs: N/A

Case#: Hove_2016_Proband_59, sex not reported, onset in early childhood, family ancestry reported as Danish

CasePresentingHPOs: HP:0007750 (foveal hypoplasia)

CaseHPOFreeText: The proband has a diagnosis of Aland Island eye disease and showed foveal hypoplasia in both eyes (supplement 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping may have been limited to Sanger sequencing of PCR products from the CACNA1F gene, or may have performed screening of other known genes associated with this phenotype.

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 panel-based sequencing of other inherited retinal disease-associated genes.

Variant: The individual harbors the NM_145200.5(CABP4):c.773A>T (p.Asn258Ile) variant in the homozygous state.

ClinVar ID: 636004

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.000001695 in the European (non-Finnish) population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/chr11-67458492-A-T?dataset=gnomad_r4

VariantEvidence: NM_145200.5(CABP4):c.773A>T (p.Asn258Ile) is a missense variant that does not have a characterized functional impact on CABP4..

CaseAddInfo: No details are available regarding the potential for parental consanguinity.

CasePMIDs: N/A

Case#: Benaglio_2014_Proband_001-417, sex not reported, age not reported, national origin German

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been diagnosed with autosomal dominant retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband consisted of screening either by Sanger sequencing of 90% of known adRP genes, by genotyping microarray of known RP variants, or sequencing-based genotyping of RHO, RDS, PRPF31, RP1, PRPF8, IMPDH1, NRL, PRPF3, NR2E3, and SNRNP200.

CaseMethod1: next-generation sequencing of PRPF4 and EFTUD2 genes

CaseMethod2: Sanger sequencing of the coding regions of NHP2L1 and AAR2

CaseGenotypingMethod: Genotyping of the proband initially consisted of either Sanger sequencing of 90% of known adRP genes, genotyping microarray of known RP variants, or sequencing-based genotyping of RHO, RDS, PRPF31, RP1, PRPF8, IMPDH1, NRL, PRPF3, NR2E3, and SNRNP200. Subsequent genotyping was performed by next-generation sequencing of PRPF4 and EFTUD2 genes and Sanger sequencing of the coding regions of NHP2L1 and AAR2.

Variant: The proband harbors the NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) variant in the heterozygous state.

ClinVar ID: 865751

gnomAD: The NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) variant is found in gnomAD v4.1.0 at a frequency of 0.00006609 (90 alleles / 1180038 total alleles, with 0 homozygotes) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/9-113283207-C-G?dataset=gnomad_r4

VariantEvidence: NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) is a missense variant located 5 bp from the 3' end of exon 5 with no direct evidence of an abnormal impact on the PRPF4 protein.

CaseAddInfo: The proband has an affected sibling who also harbors the variant.

CasePMIDs: N/A

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

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

CaseHPOFreeText: Age of onset was 3, while visual deterioration was found at age 6. Mental decline was found at age 7, while abolished ERG and Giant flash visual evoked potentials were present at age 8. Ataxia, Seizures, and Loss of independent walking occurred at age 11. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: N/A

CaseMethod2: N/A

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

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant.

ClinVar: 2565 (homozygous)

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant is 0.00005132 (within the European non-Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77566311-G-A

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

CaseAddInfo: N/A

CasePMIDs: N/A

PMID: 30174136

FamilyLabel: Meindl_1996_Family_F47

Family#PresentingHPOs: N/A

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

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Not specified

Ethnicity: Not specified

Race: Not specifically mentioned

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

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

Family#Method2: Sanger sequencing of the RPGR locus

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

Affected: 3

Unaffected: N/A

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

PublishedLOD: N/A

eLOD: 2.4

AddSegregationInfo: N/A

ProbandLabel: Meindl_1996_Family_F47_Proband

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

ClinVar: 98775

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

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

FamilyAddInfo: N/A

FamilyPMIDs: N/A

Case#: Meindl_1996_Family_F47_Proband, male, age not specified, family origin either German or British

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy)

CaseHPOFreeText: The proband and affected family members have been diagnosed with retinitis pigmentosa, with an X-linked pattern of inheritance. 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.294C>A (p.His98Gln) variant in the hemizygous state.

ClinVar: 98775

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

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

CaseAddInfo: The proband is a member of Family 47.

CasePMIDs: N/A

PMID: 29440533

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.

PMID: 34990796

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.

ExperimentName: NR2E3 physical interaction with NRL and CRX

InteractingGene: HGNC:8002 (NRL), HGNC:2383 (CRX)

InteractionType: Physical interaction

InteractionMethod: Co-immunoprecipitation

InteractionEvidence: Immunoprecipitation of NR2E3, NRL or CRX from bovine retinal nuclear extract successfully led to co-immunoprecipitation of the others, indicating their presence in a transcriptional regulatory complex (Figure 6).

PMID: 15190009

Gene: NR2E3

HGNC: 7974

Disease: enhanced S-cone syndrome

MONDO: 0100288

InheritancePattern: autosomal recessive

Prevalence: The overall prevalence of enhanced S cone syndrome is <1 in 1,000,000 (PMID: 30900587).

Penetrance: The penetrance of enhanced S-cone syndrome has been difficult to determine accurately given the rarity of the condition.

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

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

ClinVar: 9350

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

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

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 7581387, PMID: 8641699

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: Single strand conformational polymorphism analysis

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

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

ClinVar: 98607

gnomAD: The variant is absent from gnomAD version 2.1.1.

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

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 7581387, PMID: 8641699

Case#: Perrault_2000_Family_9_Proband, male, age unknown, family origin in Algeria with Arab ancestry

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

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

ClinVar: 9350

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

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

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 7581387, PMID: 8641699

PMID: 26321862

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

DiseaseAssertion: Sorsby's fundus dystrophy

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

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

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

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

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

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

PreviouslyPublished: N/A

SupplementalData: N/A

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

CAID: CA411540149

gnomAD: Variant is absent from gnomAD.

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

NonPatientCell: COS-7 cells (EFO:0001643, CLO:0002597)

GeneFunction: GO:0008191 (metalloendopeptidase inhibitor activity), GO:0046872 (metal ion binding), GO:0002020 (protease binding), GO:0005615 (active in extracellular space), GO:0031012 (active in extracellular matrix)

GeneAlteration: A TIMP3 expression construct encoding the "Ser181Cys" variant (more accurately referred to as a Ser204Cys variant) was generated by PCR using a 3' primer that contained the desired substitution.

FunctionalEvidence: The TIMP3 variant was exogenously expressed in COS-7 cells alongside a mock transfected control (not a wild-type control). Reverse zymography of extracellular matrix from these cells revealed the presence of both a monomeric and a dimeric species with metalloproteinase inhibitory activity (Figure 4). This was confirmed by immunoblotting to be TIMP3, and the dimeric species appeared under non-reducing conditions but disappeared under reducing conditions (Figure 5). This indicated that the free cysteine present in the variant may not have compromised metalloproteinase inhibitory activity, but likely facilitated an intramolecular disfulfide bonding interaction with another TIMP3 molecule. This gain-of-function interpretation of the variant effect would be consistent with the autosomal dominant mechanism of its inheritance. The wild-type control was absent from this figure. It is not clear whether a separate but similar figure showing the wild-type control was performed under reducing or non-reducing conditions.

FAVariants: Variant used was equivalent to NM_000362.5(TIMP3):c.610A>T (p.Ser204Cys) (ClinVarID:12676). The variant is referred to in this publication 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.

Case#: Gong_2001_Proband_3, 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.1468del (p.Asp490fs) variant in the homozygous state.

ClinVar: 6270

gnomAD: The NM_002335.4(LRP5):c.1468del (p.Asp490fs) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.1468del (p.Asp490fs) is a frameshift variant in exon 7 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~70% of the protein product.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

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.

Case#: Gong_2001_Proband_6, 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.3804del (p.Glu1270fs) variant in the homozygous state.

ClinVar: 6273

gnomAD: The NM_002335.4(LRP5):c.3804del (p.Glu1270fs) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.3804del (p.Glu1270fs) is a frameshift variant in exon 18 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~21% 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#: Gong_2001_Proband_1, 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.29G>A (p.Trp10Ter) variant in the homozygous state.

ClinVar: 6268

gnomAD: The NM_002335.4(LRP5):c.29G>A (p.Trp10Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.29G>A (p.Trp10Ter) is a nonsense variant in exon 1 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~99% of the protein product.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

PMID: 21654732

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 87 with choroidal involvement

MONDO: 0032873

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of Retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.

Penetrance: Incomplete penetrance, estimated at 80%

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

PMID: 10393029

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: 28207750

Gene: IFT140

HGNC: 29077

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

MONDO: 0009964

InheritancePattern: autosomal recessive

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

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

ExperimentName: OPN1LW rescue of mice with Opn1mw and Opn1sw defects

RescueModel: Mus musculus

GeneAlteration: Rescue was performed by replacing the endogenous Opn1mw gene with a known benign OPN1LW LIAIS compound variant from unaffected humans, which serves as a wild-type OPN1LW control.

RescueVariant: Rescue was performed by replacing the endogenous Opn1mw gene with a known benign OPN1LW LIAIS compound variant from unaffected humans, which serves as a wild-type OPN1LW control.

RescuePhenotype: The rescued phenotypes are cone outer segment length and number.

RescueMethod: This rescue model has replacement of the mouse Opn1mw gene with a normal variant of human OPN1LW.

RescueEvidence: Replacement of the mouse Opn1mw gene with a normal variant of human OPN1LW results in a shift in sensitivity to detect red wavelengths (Figure 5) and rescues a defect in outer segment length caused by knockout of both Opn1mw and Opn1sw (Figure 13).

ModelVariant: The model harbors homozygous deletion of Opn1sw and either intact Opn1mw or replacement of Opn1mw with human OPN1LW.

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: 32783370

Gene: KCNJ13

HGNC: 6259

Disease: Leber congenital amaurosis 16

MONDO: 0013613

InheritancePattern: autosomal recessive

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

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

Case#: 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: 33169370

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

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

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

PMID: 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.

Case#: Riazuddin_2006_Family_61019_patient_20, female, age 18 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 all four 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 61019 harbor the NM_000440.3(PDE6A):c.769C>T (p.Arg257Ter) variant in the homozygous state.

ClinVar: 437984

gnomAD: In gnomAD v2.1.1, NM_000440.3(PDE6A):c.769C>T (p.Arg257Ter) has a frequency of 0.0001633 (5/30612) in the South Asian population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/5-149310680-G-A

VariantEvidence: NM_000440.3(PDE6A):c.769C>T (p.Arg257Ter) is a nonsense variant in exon 4 of 22 that is predicted to trigger nonsense-mediated decay or at least to truncate ~70% of the protein product.

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

CasePMIDs: N/A

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

Case#: Xin_Patient_5, sex not mentioned, age 17 at onset, U.S. nationality, admixed European non-Finnish ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0003581 (Adult onset), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 17). Visual loss (age 18), Cognitive regression (age 25), and seizure (age 18) subsequently developed. Granular type inclusions were observed in blood by electron microscopy. Fingerprint inclusions were observed in the brain.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: as mentioned

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

Variant: The patient harbors the NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) variant as well as a chromosomal deletion that includes exon 4.

ClinVar: 2570 (in trans with exon 4 deletion with undefined boundaries)

gnomAD: Maximum allele frequency for NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) is 0.00002784 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77575001-A-G

VariantEvidence: The variant encodes a missense substitution that adds a cysteine to the CLN5 protein and may disrupt its structure. In a previous publication from an overlapping group of authors, mass spectrometry confirmed absence of CLN5 protein expression in samples from an individual harboring this variant, but in not control samples (PMID:19383612).

CaseAddInfo: Although parents do not appear to have been genotyped, the missense variant (in exon 4) can be inferred to be in trans with the exon 4 deletion.

CasePMIDs: N/A

Case#: Xin_Patient_3, sex not mentioned, age 17 at onset, U.S. nationality, admixed European non-Finnish ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0003581 (Adult onset), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003226 (Rectilinear intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Cognitive regression was the phenotype at presentation (age 17). Visual loss (age 20), motor difficulty (age 23), and seizure (age 23) subsequently developed. Granular type inclusions were observed by electron microscopy. Fingerprint inclusions were observed in the skin, rectilinear inclusions were observed in the muscle, and curvilinear inclusions were observed in neurons, glial cells, muscle, and spleen.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: as mentioned

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

Variant: The patient harbors the NM_006493.4(CLN5):c.230G>A (p.Cys77Tyr) and NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) variants.

ClinVar: 2569, 2570

gnomAD: The NM_006493.4(CLN5):c.230G>A (p.Cys77Tyr) variant is not found in gnomAD. Maximum allele frequency for NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) is 0.00002784 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77575001-A-G

VariantEvidence: Both variants encode missense substitutions in the protein product. Because both change the total number of cysteines in the CLN5 protein, they may disrupt its structure. In a previous publication from an overlapping group of authors, mass spectrometry confirmed absence of CLN5 protein expression in samples from this individual, but in not control samples (PMID:19383612).

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

CasePMIDs: 19383612

PMID: 20157158

Gene: CLN5

HGNC: 2076

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

MONDO: 0009745

InheritancePattern: Autosomal Recessive

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

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

PMID: 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

ExperimentName: The Cpfl1 mouse harbors loss-of-function variants in the Pde6c gene.

NonHumanModel: Mus musculus

GeneAlteration: The model animals are homozygous for two different loss-of-function variants predicted to introduce premature stop codons into the Pde6c locus. One is a 116-bp insertion between exons 4 and 5, while the other is a 1-bp deletion in exon 7.

ModelPhenotype: HP:0008020 (cone dystrophy), HP:0030465 (Undetectable light-adapted electroretinogram), normal dark-adapted ERG, rapid and progressive loss of cone photoreceptors from the photoreceptor layer

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

ModelEvidence: This is a naturally occurring mouse model with lack of light-adapted ERG responses and normal dark-adapted ERG responses (Figure 1). The mice also exhibit rapid and progressive loss of cone photoreceptors from retinal sections (Figure 2).

ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied naturally occurring variants disrupting the Pde6c locus.

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.

Selection B- Gene function is consistent with phenotype.

Title: ADAM9 enhances protelytic shedding of membrane protein ectodomains.

GOterm: GO:0006509 (membrane protein ectodomain proteolysis), GO:0045765 (regulation of angiogenesis)

FunctionalEvidence: ADAM9 over-expression in COS-7 cells enhances proteolytic shedding of membrane proteins involved in angiogenesis (Figure 5). This effect is further enhanced by reactive oxygen species (Figures 6, 7).

FunctionalHPO: HP:0007843 (Attenuation of retinal blood vessels), HP:0000546 (Retinal degeneration)

PhenotypeEvidence: This evidence is consistent with attenuation of retinal blood vessels observed in human patients as well as the finding from this same paper that Adam9 knockout mice exhibit reduced ocular neovascularization (Figures 1, 3).

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.

Case#: Leroy_2009_Family_A_Patient_III-14, male, age 58 years, family of Flemish ethnicity and Belgian national origin

CasePresentingHPOs: HP:0030640 (Complete congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0007984 (Electronegative electroretinogram), HP:0000639 (Nystagmus), HP:0003593 (Infantile onset), HP:0025404 (Abnormal visual fixation), HP:0000545 (Myopia), HP:0001104 (Macular hypoplasia), HP:0001417 (X-linked inheritance)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000613 (Photophobia), HP:0030526 (Severe constriction of peripheral visual field), HP:0030602 (Abnormal fundus autofluorescence imaging), HP:0025158 (Hyperautofluorescent retinal lesion)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing of PCR amplified exons from NYX

CaseMethod2: Haplotype analysis using microsatellite markers surrounding the NYX locus, in multiple apparently unrelated patients sharing the same variant

CaseGenotypingMethod: The proband and family members were subjected to Sanger sequencing of NYX to identify the variant, followed by haplotype analysis in comparison to apparently unrelated patients harboring the same variant.

Variant: The proband harbors the NM_022567.2:c.856del (p.Asp286ThrfsTer62) variant on the X chromosome.

CAID: CA2573050962

gnomAD: NM_022567.2:c.856del (p.Asp286ThrfsTer62) was not found in gnomAD.

VariantEvidence: The NM_022567.2:c.856del (p.Asp286ThrfsTer62) variant is located in exon 2/2 and is not predicted to trigger NMD. It is predicted to introduce a premature stop codon that would disrupt the C-terminal 41% of the protein product while adding 62 different amino acids.

CaseAddInfo: The proband comes from a large family with inheritance through an unaffected carrier mother and transmission to a grandson through an unaffected carrier daughter. This variant appears in 3 different families of Flemish Belgian origin, and is suspected to be a founder mutation in this population.

CasePMIDs: N/A

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#: Xu_2012_Patient_SRF92, male, 11 years of age at time of study, of Chinese ethnicity

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000556 (Retinal dystrophy), HP:0000580 (Pigmentary retinopathy), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0001105 (Retinal atrophy), HP:0000026 (Male hypogonadism)

CaseHPOFreeText: This proband was diagnosed with Leber congenital amaurosis, and has mild fatty liver disease.

CaseNotHPOs: HP:0000924 (Abnormality of the skeletal system), HP:0000077 (Abnormality of the kidney)

CaseNotHPOFreeText: N/A

CasePreviousTesting: It is not clear whether the patient was previously subjected to genotyping.

CaseMethod1: Whole exome sequencing

CaseMethod2: Sanger sequencing of IFT140

CaseGenotypingMethod: The patient and family members were genotyped by whole exome sequencing and confirmed by Sanger sequencing of IFT140.

Variant: The patient is a compound heterozygote harboring the paternal NM_014714.3(IFT140):c.1655_1656del (p.Glu522Glyfs6) and maternal NM_014714.3(IFT140):c.2368G>A (p.Glu790Lys) variants in IFT140*.

CAID: CA2201732453, CA7813927

gnomAD: The NM_014714.3(IFT140):c.1655_1656del (p.Glu522Glyfs*6) variant was not found in gnomAD. The NM_014714.3(IFT140):c.2368G>A (p.Glu790Lys) variant is present in gnomAD at a frequency of 0.0001087 in the East Asian population (2/18394, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1607967-C-T

VariantEvidence: NM_014714.3(IFT140):c.1655_1656del (p.Glu522Glyfs*6) is a frameshift variant that introduces a premature stop codon in exon 15/31 and is predicted to trigger NMD or at least to truncate ~64% of the protein product. NM_014714.3(IFT140):c.2368G>A (p.Glu790Lys) is a missense variant that does not have functional evidence of gene impact.

CaseAddInfo: The proband's parents are each heterozygous for one variant.

CasePMIDs: N/A

Case#: Xu_2012_Patient_SRF71, male, 43 years of age at time of study, of Han Chinese ethnicity

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000662 (Nyctalopia), HP:0000572 (Visual loss), HP:0007737 (Bone spicule pigmentation of the retina), HP:0030609 (Photoreceptor layer loss on macular OCT)

CaseHPOFreeText: This proband was diagnosed with retinitis pigmentosa.

CaseNotHPOs: HP:0000924 (Abnormality of the skeletal system), HP:0001410 (Decreased liver function), HP:0000077 (Abnormality of the kidney)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The patient was previously subjected to retinal capture sequencing focused on genes known to be associated with retinitis pigmentosa, without detecting suspected pathogenic variants.

CaseMethod1: Whole exome sequencing

CaseMethod2: Sanger sequencing of IFT140

CaseGenotypingMethod: Following the failure of retinal capture sequencing to identify retinitis pigmentosa gene variants, the patient and family members were genotyped by whole exome sequencing and confirmed by Sanger sequencing of IFT140.

Variant: The patient is a compound heterozygote harboring the paternal NM_014714.4(IFT140):c.1898_1901del (p.Asn633fs) and maternal NM_014714.4(IFT140):c.4196T>C (p.Leu1399Pro) variants in IFT140.

ClinVar: 446312, 446311

gnomAD: The NM_014714.4(IFT140):c.1898_1901del (p.Asn633fs) variant was not found in gnomAD. The NM_014714.4(IFT140):c.4196T>C (p.Leu1399Pro) variant is present in gnomAD at a frequency of 0.0001578 in the East Asian population (3/19014, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1561138-A-G

VariantEvidence: NM_014714.4(IFT140):c.1898_1901del (p.Asn633fs) is a frameshift variant that introduces a premature stop codon in exon 16/31 and is predicted to trigger NMD or at least to truncate ~57% of the protein product. NM_014714.4(IFT140):c.4196T>C (p.Leu1399Pro) is a missense variant that does not have functional evidence of gene impact.

CaseAddInfo: The proband's parents are each heterozygous for one variant, while his unaffected sister does not harbor a variant.

CasePMIDs: N/A

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).

ExperimentName: Altered pattern of splicing speckles in patient fibroblasts harboring a heterozygous p.Pro315Leu variant in PRPF4

PatientCell: CL:0000057 (fibroblast)

GeneFunction: GO:0000398 (mRNA splicing, via spliceosome)

GeneAlteration: Cells harbor a heterozygous p.Pro315Leu variant in PRPF4.

FunctionalEvidence: Patient cells harboring the variant exhibit a much higher level of endogenous marker of splicing speckles (SC-35) with a diffused distribution rather than a pattern of distinct speckles (Figures 4B and 4C). RT-PCR showed increased expression of SRSF1 and SRSF2 as well (Figure 4A). Collectively, the patient cells harboring the variant show molecular evidence of disrupted splicing.

FAVariants: The model harbors the NM_001244926.2(PRPF4):c.941C>T (p.Pro314Leu) variant in the heterozygous state (ClinVar ID: 143057).

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.