Case#: F2-II:1, F, Age: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007994 (Peripheral visual field loss), HP:0032037 (Mildly reduced visual acuity), HP:0001328 (Specific learning disability/earning difficulties)

CaseHPOFreeText: FAF imaging in three patients demonstrated a ring of increased autofluorescence parafoveally in F2-II:1

OCT imaging also demonstrated loss of outer retina with partial preservation of the inner segment ellipsoid band in patient F2-II:1

Patients from families 2 and 3 initially developed nyctalopia, with a range of onset from 9 to 30 years before subsequent development of peripheral visual field loss. At last review (age range, 24–45 years), there was mild visual acuity loss with best-corrected visual acuity mean 0.34 logMAR (range, 0.30–0.48). All patients developed posterior subcapsular cataract. Patient F2-II:1 had learning difficulties but no other symptoms suggestive of syndromic disease. There were fundus abnormalities consistent with RP including attenuated vessels, macular and midperipheral RPE mottling/atrophy, and peripheral intraretinal pigment migration, most prominent in the proband of family 3 (Fig. 2I). Fundus autofluorescence imaging demonstrated a ring of increased autofluorescence parafoveally in F2-II:1

On OCT, there was outer retinal atrophy with variable preservation of photoreceptors most apparent in F2-II:1 with a centrally preserved inner segment ellipsoid band (Fig. 2D). Optical coherence tomography imaging demonstrated intraretinal cysts of the inner nuclear layer, which responded to topical carbonic anhydrase inhibitors (Figs. 2E, 2H, 2K). Electrophysiology demonstrated rod and cone system dysfunction (Table 1).

Two affected siblings from family 2 (GC15894) were homozygous for the missense variant c.323C>G:p.(Pro108Arg).

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

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

All patients developed posterior subcapsular cataract.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_021831.6:c.323C>G (p.Pro108Arg).

ClinVar: 1184585.

CAID: CA346170082.

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

VariantEvidence: N/A.

CaseAddInfo: Affected sister F2-II:3 was noted to have the following:

Focal parafoveal increased autofluorescence in F2-II:3 (G), likely representing cystoid macular edema.

Very limited photoreceptor preservation for F2-II.3

Focally increased autofluorescence corresponding to macular edema in F2-II:3

CasePMIDs: N/A.

PMID: 18775863

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#: Mancini_2015_Patient_III-6, female, age 52 at onset of visual symptoms, North-West Italian origin

CasePresentingHPOs: HP:0003596 (Middle age onset), HP:0002355 (Difficulty walking), HP:0001260 (Dysarthria), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001272 (Cerebellar atrophy), HP:0006855 (Cerebellar vermis atrophy), HP:0008278 (Cerebellar cortical atrophy), HP:0001251 (Ataxia), HP:0002317 (Unsteady gait), HP:0000639 (Nystagmus), HP:0001310 (Dysmetria), HP:0007350 (Hyperreflexia in upper limbs), HP:0002395 (Lower limb hyperreflexia), HP:0000736 (Short attention span), HP:0002075 (Dysdiadochokinesis), HP:0001123 (Visual field defect), HP:0030528 (Paracentral scotoma), HP:0000543 (Optic disc pallor), HP:0002346 (Head tremor)

CaseHPOFreeText: Presentation was at age 52, with visual loss (attributed to glaucoma) as the first phenotype manifested. Pale and excavated optic disc (bilateral) was consistent with severe glaucoma or previous lesion of optic nerve. Neurological symptoms were recognized at age 55 (gait instability, dysarthria, and mild cognitive deficit). Onset of slight attention deficit, nystagmus with vertical component, dysarthric slurred speech, mild head tremor, truncal ataxia, mild dysmetria and dysdiadochokinesia, ataxic gait / posture, brisk deep reflexes in all four limbs, marked cerebellar atrophy (particularly in the vermis), severe bilateral cortical atrophy (especially parietal and temporal), limited visual field (bilateral, with paracentral scotoma in the left eye only), and pale and excavated optic discs (bilateral) were found at age 58. Dysarthria worsened at age 61, when patient also exhibited an inability to walk unassisted, severe intentional tremor in the limbs, and severe cognitive impairment.

CaseNotHPOs: HP:0410280 (Pediatric onset), HP:0003474 (Somatic sensory dysfunction), HP:0002353 (EEG abnormality), HP:0040129 (Abnormal nerve conduction velocity),

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing was limited to molecular tests ruling out Friedreich Ataxia and Spinocerebellar Ataxia types 1 and 2.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Whole exome sequencing of the proband and the affected sibling. Homozygosity was assumed due to the consanguinity of the family, contributing to the decision to focus on the variant in CLN5. This variant was confirmed by Sanger sequencing of PCR products from exon 4 of the CLN5 gene in both affected family members and an additional unaffected sibling. Parents were not subjected to genotyping.

Variant: The proband is homozygous for the NM_006493.4(CLN5):c.788G>A (p.Ser263Asn) variant.

ClinVar: 183049 (homozygous)

gnomAD: The maximum allele frequency for the NM_006493.4(CLN5):c.788G>A (p.Ser263Asn) variant is 0.000008805 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/13-77574815-G-A

VariantEvidence: The variant encodes a missense substitution that results in aberrant retention in the ER compartment rather than proper localization to lysosomal vesicles (Figs. 1E-1J).

CaseAddInfo: Family is consanguineous (parents were first cousins).

CasePMIDs: N/A

PMID: 27302685

review article

Case#: Gong_2001_Proband_2, 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.1282C>T (p.Arg428Ter) variant in the homozygous state.

ClinVar: 6269

gnomAD: The NM_002335.4(LRP5):c.1282C>T (p.Arg428Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.1282C>T (p.Arg428Ter) is a nonsense variant in exon 6 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~74% of the protein product.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

Case#: Gong_2001_Proband_4, 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.2151dup (p.Asp718Ter) variant in the homozygous state.

ClinVar: 6271

gnomAD: The NM_002335.4(LRP5):c.2151dup (p.Asp718Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.2151dup (p.Asp718Ter) is a nonsense variant in exon 10 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~56% of the protein product.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

Case#: Aldahmesh_2010_Family_Proband_II-1, male, onset in early childhood, age 12 years at time of report, family ancestry reported as Dutch

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity), HP:0000613 (Photophobia), HP:0000551 (Color vision defect)

CaseHPOFreeText: The proband and his sibling have a diagnosis of cone-rod dysfunction, including color vision described as severely abnormal and electroretinogram responses that showed absent cone a-wave but normal-to-subnormal rod function.

CaseNotHPOs: HP:0000662 (Nyctalopia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to homozygosity mapping of the sibling and his affected sister that identified a shared region of homozygosity on chromosome 13.

CaseMethod1: Homozygosity mapping

CaseMethod2: Sanger sequencing of CABP4

CaseGenotypingMethod: Genotyping began with homozygosity mapping of the sibling and his affected sister that identified a shared region of homozygosity on chromosome 13, followed by Sanger sequencing of PCR products from the CABP4 gene.

Variant: The individual harbors the NM_145200.5(CABP4):c.646C>T (p.Arg216Ter) variant in the homozygous state.

ClinVar ID: 190959

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.0001418 in the European (non-Finnish) population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/chr11-67457677-C-T?dataset=gnomad_r4

VariantEvidence: NM_145200.5(CABP4):c.646C>T (p.Arg216Ter) is a nonsense variant within exon 4 of 6 that is predicted to trigger nonsense-mediated decay.

CaseAddInfo: The proband's family includes a similarly affected sister harboring the variant in the homozygous state, and unaffected parents who each carry the variant in the heterozygous state. Consanguinity has not been commented upon.

CasePMIDs: N/A

PMID: 32203983

GeneName: GNAT2

HGNC: 4394

Disease: achromatopsia 4

MonDO ID: MONDO_0013465

Inheritance: autosomal recessive

FamilyLabel: Corton_2010_Family_RP-72

Family#PresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000540 (Hypermetropia), HP:0007663 (Reduced visual acuity), HP:0001133 (Constriction of peripheral visual field), HP:0000550 (Undetectable electroretinogram), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007401 (Macular atrophy), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor)

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with retinitis pigmentosa segregating with an autosomal recessive mode of inheritance.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Spain / Galicia

Ethnicity: Spanish

Race: Not specifically described

Family#PreviousTesting: N/A

Family#Method1: Haplotype analysis

Family#Method2: Sanger sequencing of 3 candidate genes; PDE6A, PDE6B, and RHO

Family#GenotypingMethod: Haplotype analysis was performed in affected and unaffected family members to identify candidate regions of homozygosity in all affected individuals. Sanger sequencing was then performed on PCR products of exons and flanking regions from the PDE6A, PDE6B, and RHO loci.

Affected: 4

Unaffected: 5 fully genotyped

Segregations: 4 segregations are shown by the pedigree in Figure 1a.

PublishedLOD: N/A

eLOD: 2.43

AddSegregationInfo: N/A

ProbandLabel: Corton_2010_Family_RP-72_patient_IV:2

Variant: The affected family members harbor the NM_000440.3(PDE6A):c.2053G>A (p.Val685Met) variant in the homozygous state.

ClinVar: 29874

gnomAD: In gnomAD v2.1.1, NM_000440.3(PDE6A):c.2053G>A (p.Val685Met) has a frequency of 0.00008531 (11/128938) in the European non-Finnish population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/5-149263074-C-T

VariantEvidence: A mutation equivalent to this variant in the homozygous nmf28/nmf28 mouse model caused grainy abnormalities in fundus pigmentation associated with loss of most photoreceptor cells shortly after birth, as well as loss of cGMP-PDE6 activity resulting in increased intracellular cGMP levels (PMID: 18849587).

FamilyAddInfo: The family includes multiple consanguineous unions, including the proband's parents, and three affected paternal aunts.

FamilyPMIDs: N/A

PMID: 25085631

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: Rescue in patient-derived IPSC cells harboring IFT140 variants

RescueProband: Forbes_2018_Proband_1 has been diagnosed with retinitis pigmentosa (age 1), end-stage kidney disease (age 6), and Mainzer-Saldino syndrome (at the time of this study). The proband and her non-consanguineous parents were genotyped by Trio whole exome sequencing, identifying compound heterozygous (paternal and maternal) IFT140 variants in the proband.

GeneAlteration: The proband harbors the NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) and NM_014714.4(IFT140):c.2176C>G (p.Pro726Ala) variants in trans. The former variant has been shown to mislocalize when exogenously expressed as a cDNA, and is predicted to disrupt a donor splice site (SpliceAI change score of 0.61).

RescueVariant: The variant rescued by CRISPR/Cas9-based gene editing was NM_014714.4(IFT140):c.634G>A (p.Gly212Arg), (ClinVar ID: 31683). This variant was corrected at the same time as a synonymous 3 bp change was introduced to facilitate the detection of the editing event.

RescuedPhenotype: Patient IPSC-derived organoids exhibit Short / clubbed cilia with swollen sips (Figure 3A-3C), Approximately 50% expression of IFT140 at both the mRNA and protein levels (Figures 2D, 2E), and Disturbed apicobasal polarity compromising the ability of iPSC cells to establish polarized spheroids (Figures 5C, 5D).

RescueMethod: CRISPR/Cas9-based gene editing was used to correct one of the proband's two variants (NM_014714.4(IFT140):c.634G>A (p.Gly212Arg), (ClinVar ID: 31683)). A synonymous 3 bp change was simultaneously introduced to facilitate the detection of the editing event.

RescueEvidence: Gene-corrected cells had longer ciliary length with reduced clubbing (Figure 3), approximately twice the expression of IFT140 at the mRNA and protein levels (Figures 2D, 2E), and a higher percentage of polarized spheroids established in organoid culture (indicating recovery of apicobasal polarity).

PMID: 19853238

Gene: BEST1

PMID: 24069149

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.

ExperimentName: Morpholino-based knockdown of zbbs1 disrupts ciliary beating pattern.

NonHumanModel: Danio rerio

GeneAlteration: The model animals have been subjected to morpholino-based knockdown of zbbs1, the zebrafish ortholog of human BBS1.

ModelPhenotype: HP:0012262 (Abnormal ciliary motility), HP:0000107 (Renal cyst)

HumanPhenotype: HP:0000639 (Nystagmus), HP:0000510 (Rod-cone dystrophy), HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0000107 (Renal cyst), HP:0001513 (Obesity), HP:0010442 (Polydactyly), HP:0002463 (Language impairment), HP:0000026 (Male hypogonadism)

ModelEvidence: Morpholino-based knockdown of the zbbs1 gene causes hydrocephalus (Figure 3B), formation of pronephritic cysts (Figure 3G), embyronic body axis abnormalities (Figure 4B), heart looping defects (Figure 5B), longer cilia (Figure 7F), and normal ciliary ultrastructure (Figure 7I), and aberrant ciliary motility in the pronephritic tubule and nasal pit (Supplementary Movies).

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

ExperimentName: CRISPR/Cas9-based disruption of mouse Impg2

NonHumanModel: Mus musculus

GeneAlteration: Model animals were subjected to CRISPR/Cas9-based deletion of 166bp from exon 2 of Impg2, and analyzed in the homozygous state. Absence of Impg2 signal was confirmed by RT-PCR. Mice were studied at ages 3, 6, and 13 months.

ModelPhenotype: HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0000580 (Pigmentary retinopathy), HP:0030609 (Photoreceptor layer loss on macular OCT)

HumanPhenotype: HP:0000529 (Progressive visual loss), HP:0000662 (Nyctalopia), HP:0000551 (Color vision defect), HP:0008002 (Abnormality of macular pigmentation), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0000533 (Chorioretinal atrophy), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007994 (Peripheral visual field loss), HP:0000603 (Central scotoma)

ModelEvidence: Abnormalities of the homozygous Impg2 deletion mice included reduction in the amplitudes of ERG responses from both rods and cones at age 6 months (Figure 2). Pigmentary retinopathy was also observed (Figure 2C), as well as progressive photoreceptor layer loss (Figure 3). Cone markers such as PNA and M-opsin were mislocalized (Figure 4), indicating cone cell disorganization. Enhanced apoptosis was also observed in the photoreceptor cell segments (Figure 5), consistent with the decreased outer nuclei layer thickness.

ModelVariant: The model does not introduce a variant previously observed in human patients, but rather disrupts the expression of the Impg2 ortholog.

PMID: 19536307

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

Case#: Bravo-Gil_2016_Proband_95, sex not specified, age 7 years at onset, family origin reported as Spanish

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0001133 (Constriction of peripheral visual field), and HP:0000662 (Nyctalopia), HP:0000550 (Undetectable electroretinogram), HP:0410280 (Pediatric onset)

CaseHPOFreeText: The proband is part of an inherited retinal disease cohort and received an initial diagnosis of simplex retinitis pigmentosa. Night blindness was the first visual symptom.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: next-generation sequencing panel

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

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

Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) and NM_024649.5(BBS1):c.1474-2A>G variants in the compound heterozygous state.

ClinVar ID: 12143

CAID: CA381424925

gnomAD: The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1 The NM_024649.5(BBS1):c.1474-2A>G variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant. NM_024649.5(BBS1):c.1474-2A>G is a canonical splice site variant in intron 14 that is predicted but not confirmed to disrupt BBS1 splicing.

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

CasePMIDs: N/A

PMID: 9855162

Gene: RPGR

HGNC: 10295

Disease: RPGR-related retinopathy

MONDO: MONDO:0100437

InheritancePattern: X-linked

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

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

PMID: 23189188

ExperimentName: GPR143 silencing in melanoma cells

NonPatientCell: CL:1000458 (melanocyte of skin, specifically the highly pigmented MNT-1 human melanoma cell line)

GeneFunction: GO:1903232 (melanosome assembly)

GeneAlteration: GPR143 silencing was accomplished by transient transfection of MNT-1 cells with specific siRNA, alongside a non-targeting siRNA control.

FunctionalEvidence: siRNA-treated cells exhibited 50% reduction in mature melanosomes and melanin-containing cells by immunofluorescence (Figures 2E, 2F, 2G). This was confirmed by electron microscopy (Figures 2H, 2I, 2J, 2K). GPR143 silencing also resulted in a combination of normal sized melanosomes and enlarged macromelanosome precursors (Figures 2I, S2A). These cellular defects are an approximate match to the giant melanosomes in the melanocytes of the human patients as well as the hypopigmentation of the fundus.

FAVariants: GPR143 disruption was siRNA-based, and patient-associated variants were not studied.

PMID: 30319355

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: Morpholino-based disruption of Impg2 in medaka fish

NonHumanModel: Oryzias latipes

GeneAlteration: Model animals were subjected to targeted disruption of Impg2 by morpholino-based silencing.

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

HumanPhenotype: HP:0000529 (Progressive visual loss), HP:0000662 (Nyctalopia), HP:0000551 (Color vision defect), HP:0008002 (Abnormality of macular pigmentation), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0000533 (Chorioretinal atrophy), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007994 (Peripheral visual field loss), HP:0000603 (Central scotoma)

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

ModelVariant: The model does not introduce a variant previously observed in human patients, but rather disrupts the expression of the Impg2 ortholog using a morpholino.

Case#: Olivier_2021_Family_K_Proband_II:3, male, age 43 years at the time of onset, national origin reported as Spanish

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0001099 (Fundus atrophy), HP:0007737 (Bone spicule pigmentation of the retina)

CaseHPOFreeText: The proband has onset of retinitis pigmentosa at the age of 43 years.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: It is not clear whether previous testing methods included systematic genotyping of loci associated with VMD or RP.

CaseMethod1: Screening of IMPG1 using either gene panel testing or exome sequencing

CaseMethod2: Sanger sequencing-based confirmation

CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus and Sanger sequencing-based confirmation.

Variant: The proband harbors the NM_001563.4(IMPG1):c.1982G>A (p.Arg661His) variant in the homozygous state.

ClinVar ID: 1056230

gnomAD: The NM_001563.4(IMPG1):c.1982G>A (p.Arg661His) variant is found in gnomAD v2.1.1 at a frequency of 0.00004006 (1/24964) in the African / African-American population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76657093-C-T

VariantEvidence: NM_001563.4(IMPG1):c.1982G>A (p.Arg661His) is a missense variant, which does not have experimental evidence of a functional effect on the protein product.

CaseAddInfo: The patient's affected sister shares the same homozygous genotype.

CasePMIDs: N/A

Case#: Olivier_2021_Family_H_Proband_II:1, male, age 53 years at the time of diagnosis, national origin reported as French

CasePresentingHPOs: HP:0007401 (Macular atrophy), HP:0007737 (Bone spicule pigmentation of the retina)

CaseHPOFreeText: The proband has been diagnosed with maculopathy at the age of 53 years, and exhibits retinal discoloration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: It is not clear whether previous testing methods included systematic genotyping of loci associated with VMD or RP.

CaseMethod1: Screening of IMPG1 using either gene panel testing or exome sequencing

CaseMethod2: Sanger sequencing-based confirmation

CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus and Sanger sequencing-based confirmation.

Variant: The proband harbors the NM_001563.4:c.2083G>T (p.Glu695Ter) variant in the heterozygous state.

CAID: CA364770054

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

VariantEvidence: NM_001563.4:c.2083G>T (p.Glu695Ter) is a nonsense variant in exon 15 of 17, which is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 13% of the protein product.

CaseAddInfo: The patient's brother is an unaffected carrier of the variant.

CasePMIDs: N/A

PMID: 12506099

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.

ExperimentName: Naturally occurring mouse model of Nyx loss-of-function

NonHumanModel: Mus musculus

GeneAlteration: This naturally occurring model, previously known to exhibit the absence of b-wave in ERG recordings, harbors an 85-bp deletion in the final exon of the Nyx gene that shifts the frame and replaces the C-terminal 61% of the protein product with 170 novel amino acids. The predicted effect is loss-of-function.

ModelPhenotype: HP:0007984 (Electronegative electroretinogram), HP:0000649 (Abnormality of visual evoked potentials), HP:0007663 (Reduced visual acuity), HP:0001419 (X-linked recessive inheritance)

HumanPhenotype: HP:0030640 (Complete congenital stationary night blindness), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0007642 (Congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)

ModelEvidence: The model exhibited reduced amplitude of dark-adapted bright flash electroretinogram b-wave (electronegative ERG) but normal amplitude of the a-wave (PMID: 9804152). Visually-driven cortical activity was also abnormal (9804152). Visual acuity was also reduced (Figure 4). Inheritance was X-linked recessive (Figure 3), which also matches the human families.

ModelVariant: The model is naturally occurring, and so the affected animals harbor a variant that does not have an exact human patient equivalent.

Case#: Morimura_1998_Family_9148_Patient_II-1, male, 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 compound heterozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.118G>A (p.Gly40Ser) and NM_000329.3(RPE65):c.544C>T (p.His182Tyr) variants.

ClinVar: 98830, 98875

gnomAD: The NM_000329.3(RPE65):c.2T>C (p.Met1Thr) variant has a maximum allele frequency of 0.00009643 (within the Ashkenazi Jewish population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68912520-C-T The NM_000329.3(RPE65):c.544C>T (p.His182Tyr) variant has a maximum allele frequency of 0.00009925 (within the Ashkenazi Jewish population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68906635-G-A

VariantEvidence: The paternal NM_000329.3(RPE65):c.118G>A (p.Gly40Ser) and maternal NM_000329.3(RPE65):c.544C>T (p.His182Tyr) variants are missense variants that do not have evidence of gene impact.

CaseAddInfo: Genotyping of family members revealed the two variants to be in trans. The brother of the proband shares the same genotype and diagnosis of Leber congenital amaurosis.

CasePMIDs: N/A

PMID: 9501220

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

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

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

Case#: Morimura_1998_Family_3867_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 compound heterozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) and NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) variants.

ClinVar: 13115, 98862

gnomAD: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant has a maximum allele frequency of 0.0002406 (within the African / African-American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68910541-G-A The NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) variant is not found within gnomAD.

VariantEvidence: NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) is a missense variant that does not have evidence of gene impact. The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant was also detected in this publication in a heterozygous state within two apparently unrelated probands with Retinitis pigmentosa (Figure 2A) and Leber congenital amaurosis (Figure 2B), respectively. A separate publication (PMID: 16754667) expressed this missense variant in non-patient cells and showed that it abolished the isomerohydrolase activity of the protein product, reduced its stability, and shifted the subcellular localization from predominantly membrane-associated to predominantly cytosolic.

CaseAddInfo: Genotyping of the proband's parents revealed NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) as the paternal variant and NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) as a de novo variant.

CasePMIDs: N/A

PMID: 9501220

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: 18179896

Gene: KCNJ13

HGNC: 6259

Disease: snowflake vitreoretinal degeneration

MONDO: 0008663

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of snowflake vitreoretinal degeneration is ~1 in 1,000,000 (https://www.orpha.net/en/disease/detail/91496).

Penetrance: Known disease-causing alleles appear to be completely penetrant (PMID: 14644728).

Case#: Bech-Hansen_2000_Patient_610-1, male, age and race not mentioned, national origin in Costa Rica

CasePresentingHPOs: HP:0030640 (Complete congenital stationary night blindness)

CaseHPOFreeText: Patients in this study have a diagnosis of complete congenital stationary night blindness. Although this implies nyctalopia and photopic vision loss, specific phenotypic details are absent.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: FokI restriction enzyme digestion of the relevant PCR product to monitor segregation in the proband and family members

CaseMethod2: Sanger sequencing of PCR amplified exons from NYX

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

Variant: The proband harbors the NM_001378477.3(NYX):c.1034G>A (p.Trp345Ter) variant on the X chromosome.

ClinVar: 11421

gnomAD: NM_001378477.3(NYX):c.1034G>A (p.Trp345Ter) has a maximum allele frequency of 0.00007388 (2/27070, with no males or homozygous females) in the Latino / Admixed American population. https://gnomad.broadinstitute.org/variant/X-41333755-G-A

VariantEvidence: This nonsense variant is located in the final exon and is not predicted to trigger NMD, but introduces a premature stop codon that truncates 28% of the protein product. The disrupted region is part of the predicted GPI anchor responsible for tethering the protein to the membrane.

CaseAddInfo: N/A

CasePMIDs: N/A

PMID: 12118255

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.

ExperimentName: Phenotypic characterization of the heterozygous Timp3Ser179Cys Knock-In Mouse

NonHumanModel: Mus musculus (129/Sv and hybrid C57BL/6 × 129/SvJ background)

GeneAlteration: The mouse Timp3 ortholog was subjected to site-directed mutagenesis to introduce a change equivalent to the human variant encoding the Ser179Cys substitution associated with Sorsby Fundus Dystrophy (PMID:8634721). This variant was introduced into embryonic stem cells by homologous recombination, generating animals for germline transmission of the Timp3Ser179Cys knock-in allele of interest.

ModelPhenotype: HP:0007703 (Abnormality of retinal pigmentation), Abnormalities of the inner aspect of Bruch's membrane

HumanPhenotype: HP:0007703 (Abnormality of retinal pigmentation, PMID:27601084, PMID:16989765), thickening of the inner part of Bruch's membrane

ModelEvidence: While the model system phenotype does not recapitulate all of the human SFD phenotypes, most of which represent the later stages of disease progression, it does recapitulate some early events from the human phenotype, such as abnormalities of Bruch's membrane and the retinal pigment epithelium. The retinal pigment epithelium exhibits structural abnormalities in mutant animals relative to wild-type controls, at both 8 months and 30 months. At 8 months specifically, 15%–20% of RPE areas analyzed showed loss of vertical orientation and increased distances between processes at the cellular bases (Fig. 3) . Patchy thinning of basal microvilli was observed adjacent to Bruch’s membrane, with disrupted packing of microvilli and caverns extending from the basal labyrinth (Figure 3). Timp3 western blots of RPE-choroid ECM extracts from knock-in mice also accumulated higher-molecular weight complexes of Timp3 (Figure 5), similar to the exogenously expressed human variant (PMID:10854443).

ModelVariant: The model variant is a knock-in modification to the mouse Timp3 ortholog that is equivalent to the human NM_000362.5(TIMP3):c.536C>G, (p.Ser179Cys) missense variant (ClinVar:12678). While the article refers to the variant as "Ser156Cys", the updated nomenclature should be Ser179Cys (including the 23-amino acid N-terminal signal peptide).

PMID: 12147610

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: 22503633

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.

Case#: Perrault_2012_Patient_FV1, male, 10 years of age at time of study, ethnicity not specified

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000545 (Myopia), HP:0007994 (Peripheral visual field loss), HP:0032037 (Mildly reduced visual acuity), HP:0000510 (Rod-cone dystrophy), HP:0000512 (Abnormal electroretinogram), HP:0004322 (Short stature), HP:0001363 (Craniosynostosis), HP:0030799 (Scaphocephaly), HP:0001999 (Abnormal facial shape), HP:0010230 (Cone-shaped epiphyses of the phalanges of the hand), HP:0000365 (Hearing impairment), HP:0003774 (Stage 5 chronic kidney disease), HP:0000107 (Renal cyst), HP:0004719 (Hyperechogenic kidneys), HP:0005565 (Reduced renal corticomedullary differentiation), HP:0001510 (Growth delay)

CaseHPOFreeText: This proband was diagnosed with Mainzer-Saldino syndrome.

CaseNotHPOs: HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140

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

Variant: The patient is a compound heterozygote harboring the NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) and NM_014714.4(IFT140):c.3916dup (p.Ala1306fs) variants in IFT140.

ClinVar: 31683, 31684

gnomAD: The NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) variant is present in gnomAD at a frequency of 0.00009295 in the European (non-Finnish) population (12/129100, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1642177-C-T The NM_014714.4(IFT140):c.3916dup (p.Ala1306fs) variant is present in gnomAD at a frequency of 0.0001210 in the African / African-American population (3/24790, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1570005-G-GC

VariantEvidence: Exogenous expression of the FLAG-tagged p.Gly212Arg variant in the RPE1 (retinal pigment epithelial) cell line revealed an inability to co-localize with gamma-tubulin, indicating a defect in localization to the basal body in most cells that is less severe than one of the other suspected pathogenic missense variants (Figure 3A). NM_014714.4(IFT140):c.3916dup (p.Ala1306fs) is a frameshift variant that introduces a premature stop codon in exon 28/31 and is predicted to trigger NMD or at least to truncate ~11% of the protein product.

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

CasePMIDs: N/A

Case#: Perrault_2012_Patient_FIV3, male, 17 years of age at time of study, Saudi Arabian national origin

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0000639 (Nystagmus), HP:0000729 (Autistic behavior), HP:0001250 (Seizure), HP:0008499 (High hypermetropia), HP:0001123 (Visual field defect), HP:0007663 (Reduced visual acuity), HP:0000550 (Undetectable electroretinogram), HP:0010230 (Cone-shaped epiphyses of the phalanges of the hand), HP:0000556 (Retinal dystrophy)

CaseHPOFreeText: Acetylated alpha-tubulin staining in cultured fibroblasts showed an absence of primary cilia in a high number of cells from this patient. IFT140 protein localization along the ciliary axoneme was unaffected, however, two components of the anterograde transport IFT-B complex, IFT88 and IFT46, were aberrantly localized. They were evenly distributed along the cilium instead of primarily localized at the base and the tip of the cilium, suggesting an alteration in retrograde ciliary transport.

CaseNotHPOs: HP:0004322 (Short stature), HP:0000765 (Abnormal thorax morphology), HP:0000929 (Abnormal skull morphology), HP:0040064 (Abnormality of limbs), HP:0001410 (Decreased liver function), HP:0012211 (Abnormal renal physiology), HP:0003272 (Abnormal hip bone morphology)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140

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

Variant: Affected individuals harbor the NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant in a homozygous state.

ClinVar: 31679

gnomAD: The NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant is present in gnomAD at a frequency of 0.00004031 in the African / African-American population (1/24806, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1614075-C-T

VariantEvidence: Exogenous expression of the FLAG-tagged p.Glu664Lys variant in the RPE1 (retinal pigment epithelial) cell line revealed an inability to co-localize with gamma-tubulin, indicating a relatively severe defect in localization to the basal body in most cells, relative to other suspected pathogenic missense variants and the wild-type control (Figure 3A).

CaseAddInfo: The proband's parents are reportedly consanguineous (first cousins).

CasePMIDs: N/A

Case#: Perrault_1998_Patient_I-1, male, age and ethnicity not described

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0007641 (Dyschromatopsia), HP:0000613 (Photophobia), HP:0000603 (Central scotoma), HP:0011516 (Achromatopsia), HP:0007994 (Peripheral visual field loss), HP:0007675 (Progressive night blindness), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: Onset was during the 1st decade of life. Diagnosis was autosomal dominant cone-rod dystrophy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing established linkage to the D17S1796 and D17S1881 microsatellite markers.

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

CaseMethod2: N/A

CaseGenotypingMethod: The proband and his family members were subjected to linkage analysis using the D17S1796 and D17S1881 microsatellite markers, as well as sequencing of PCR products from each of the 18 exons of the GUCY2D locus.

Variant: The proband harbors the NM_000180.3(GUCY2D):c.[2511G>C;2512C>T;2516C>T] variant in the heterozygous state.

ClinVar: 453244

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.3(GUCY2D):c.[2511G>C;2512C>T;2516C>T] is a missense variant that causes three adjacent substitutions at the protein level (p.Glu837Asp;Arg838Cys;Thr839Met), 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: 9618177, PMID: 12552567, PMID: 26298565). The p.Arg838Cys substitution has been shown to disrupt the calcium sensitivity of GUCY2D and to trigger the inability to inactivate cyclase activity at high physiological calcium ion concentrations (PMID: 11115851).

CaseAddInfo: The patient is a member of a three-generation family with affected children and grandchildren.

CasePMIDs: N/A

PMID: 9683616

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: 8981947

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

Case: Felbor_1997_Family_1_patient_III-4, gender not specified, country of origin Finland, onset not specified

DiseaseAssertion: Sorsby's fundus dystrophy

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

CasePresentingHPOs: N/A

CaseHPOFreeText: While phenotypes were not described for the specific proband, the affected family members exhibit early onset of visual loss between the second and fourth decade of life, with the first sign in young family members being uneven or absent pigmentation in the extreme fundus periphery. Affected individuals experience progressive vision loss, iris atrophy, and glaucoma in some cases.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Single-stranded conformational analysis (SSCA) of the coding and promoter regions of TIMP3, detecting a disease-specific mobility shift in exon 5. Sanger sequencing of PCR products from exon 5 of the TIMP3 gene in comparison to a control individual.

GenotypingMethod: Enzymatic digestion of TIMP3 exon 5 PCR products with the HaeIII restriction endonuclease.

PreviouslyPublished: This highly consanguineous family was previously published in PMID:7148944 and PMID:2387082. It was proposed to show an autosomal recessive pattern of inheritance (not previously observed for Sorsby fundus dystrophy). The family has been genotyped for the first time in this study, revealing segregation of disease phenotypes with a heterozygous variant in TIMP3, with autosomal dominant inheritance.

SupplementalData: N/A

Variant: Proband harbors the NM_000362.5(TIMP3):c.565G>T (p.Gly189Cys) missense variant.

ClinVar: 12679

gnomAD: Variant is absent from gnomAD.

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

Case#: II.1, F, Age of Onset: 7-8 y.o., Ethnicity: Turkish.

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa)

CaseHPOFreeText: Proband comes from a consanguineous family.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Exome sequencing.

Variant: NM_021831.6:c.883G>A (p.Asp295Asn).

ClinVar: 242932.

CAID: CA10584033.

gnomAD: Frequency: 0.000005530. Link: https://gnomad.broadinstitute.org/variant/chr2-27055228-G-A?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: The proband has two affected siblings. They were evaluated by Sanger sequencing. II.3 had age of onset at 7-8 y.o and was noted to have mixed astigmatism and mental retardation

II.4 had age of onset at 12 y.o and was noted to have

Both siblings were homozygous for the same variant as the proband.

Since targeted analysis of all genes linked to retinal disorders did not reveal a pathogenic mutation in pedigree E, we extended our search to include the entire exomes of the two affected family members. With this approach, a homozygous missense mutation (Asp295Asn) was detected in the deglutamylase gene AGBL5 which was confirmed in all affected family members while the unaffected parents are heterozygous carriers.

CasePMIDs: N/A.

PMID: 15623792

Gene: CRB1

HGNC: 2343

Disease: pigmented paravenous retinochoroidal atrophy

MONDO: 0008246

InheritancePattern: autosomal dominant

Prevalence: Orphanet defines pigmented paravenous retinochoroidal atrophy as a rare disorder with incidence lower than 1 in 1,000,000. However, the incidence is not well-reported in published papers and may be more common than this.

Penetrance: The paper reporting affected family members shows 6 affected genotype-positive individuals and 1 unaffected genotype-negative individual. On the other hand, the high frequency of the variant in gnomAD would be consistent with incomplete penetrance or low rate of diagnosis.

FamilyLabel: McKay_2005_Family, family ethnic origin reported as white

Family#PresentingHPOs: HP:0000533 (Chorioretinal atrophy), HP:0007903 (Paravenous chorioretinal atrophy), HP:0007663 (Reduced visual acuity), HP:0030469 (Abnormal dark-adapted electroretinogram)

FamilyHPOFreeText: The patient and affected family members have been diagnosed with pigmented paravenous retinochoroidal atrophy. Expressivity is very variable, but all members showed subtle symmetrical chorioretinal atrophy in the inferior quadrant as the presenting feature, with atrophy later becoming more widespread. The proband had optic disc drusen. OCT through an area of bony spicule pigmentation showed that the pigment was located in the superficial neuroretina.

Family#PresentingNotHPOs: HP:0030603 (Abnormal optical coherence tomography)

Family#PresentingNotHPOFreeText: N/A

CountryOrigin: Possibly the United Kingdom

Ethnicity: Not mentioned

Race: White

Family#PreviousTesting: Sanger sequencing of candidate genes associated with retinal degeneration was performed, with only the CRB1 locus specifically identified.

Family#Method1: Sanger sequencing of CRB1

Family#Method2: N/A

Family#GenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of candidate genes associated with retinal degeneration, including the CRB1 locus.

Affected: 6

Unaffected: 1

Segregations: Five segregations are reported in the family, with none inconsistent. The pedigree is shown in Figure 1.

PublishedLOD: 1.8

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: McKay_2005_Family_Proband_III:3

Variant: The affected family members harbor the NM_201253.3(CRB1):c.484G>A (p.Val162Met) variant in the heterozygous state.

ClinVarID: 5738

gnomAD: This variant is found in gnomAD v4.1.1 at a frequency of 0.001610 overall, with a similar frequency in the European (non-Finnish) population and 6 homozygotes overall https://gnomad.broadinstitute.org/variant/chr1-197328835-G-A?dataset=gnomad_r4

FamilyAddInfo: The family has not been reported as consanguineous.

FamilyPMIDs: N/A

Case#: Shen_2019_Patient_III-10, female, age 39 years at time of report, national origin reported as Chinese, ethnicity reported as Miao

CasePresentingHPOs: HP:0001513 (Obesity), HP:0000822 (Hypertension), HP:0000107 (Renal cyst), HP:0010442 (Polydactyly), HP:0000750 (Delayed speech and language development), HP:0000678 (Dental crowding), HP:0011342 (Mild global developmental delay), HP:0001156 (Brachydactyly), HP:0000470 (Short neck), HP:0005280 (Depressed nasal bridge), HP:0000140 (Abnormality of the menstrual cycle)

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

CaseNotHPOs: HP:0000134 (Female hypogonadism), HP:0002194 (Delayed gross motor development), HP:0000708 (Atypical behavior), HP:0000819 (Diabetes mellitus), HP:0000365 (Hearing impairment), HP:0000518 (Cataract), HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of exome sequencing.

CaseMethod1: exome sequencing

CaseMethod2: Sanger sequencing of the BBS7 locus

CaseGenotypingMethod: Genotyping consisted of exome sequencing, followed by Sanger sequencing of the BBS7 locus.

Variant: The patient harbors the NM_176824.3(BBS7):c.389_390del (p.Asn130fs) variant in the homozygous state.

ClinVar ID: 216138

gnomAD: The NM_176824.3(BBS7):c.389_390del (p.Asn130fs) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_176824.3(BBS7):c.389_390del (p.Asn130fs) is an out-of-frame deletion variant in exon 5 of 18 that is predicted to trigger nonsense-mediated decay or at least truncation of the C-terminal 82% of the protein product.

CaseAddInfo: Consanguinity in the proband's family is suspected but has not been confirmed. She has two similarly affected cousins who share the same homozygous genotype. The carrier status of her unaffected parents and an unaffected sibling have been confirmed by genotyping.

CasePMIDs: N/A

PMID: 30839500

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.

PMID: 15557452

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: 9760202

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

Case: Tabata_1998_Family_Ch_patient_1, male, 52 years of age at onset of visual symptoms, country of origin Japan

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: The proband passed on the variant to his son and likely inherited it from his affected mother (who was not genotyped).

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0025094 (Disciform macular scar), HP:0000529 (Progressive visual loss), HP:0000603 (Central scotoma)

CaseHPOFreeText: Onset of decreased central vision was seen in the 6th decade of life (both eyes between the ages of 52 and 57).

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

CaseNOTHPOFreeText: Although central vision was progressively lost, peripheral fundi have remained uninvolved and the individual has continued to walk unguided into the 8th decade of his life.

CasePreviousTesting: PCR-based heteroduplex analysis using gel electophoresis

CaseGenotypingMethod: Sanger sequencing

PreviouslyPublished: N/A

SupplementalData: N/A

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

CAID: CA1139771334

gnomAD: Variant is absent from gnomAD.

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

FamilyLabel: Tabata_1998_Family_Ue

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

FamilyHPOFreeText: Onset of decreased central vision was seen in the 8th decade of life (between the ages of 71 and 75).

FamilyNotHPOs: HP:0007994 (Peripheral visual field loss)

FamilyNotHPOFreeText: Although central vision was decreased, peripheral fundi remained uninvolved.

CountryOrigin: Japan

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

Family#GenotypingMethod: Sanger sequencing

Affected: 3

Unaffected: 0

Segregations: N/A

PublishedLOD: N/A

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Tabata_1998_Family_Ue_patient_1

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

CAID: CA1139771334

gnomAD: Variant is absent from gnomAD.

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

FamilyPMIDs: N/A

PMID: 10951519

Gene: GUCY2D

HGNC: 4689

Disease: Leber congenital amaurosis 1

MONDO: 0008764

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by GUCY2D variants is between 10% and 20% (PMID: 10951519). Thus, the prevalence of Leber congenital amaurosis 1 is between 1 in 165,000 and 1 in 1,000,000.

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

Case#: Linder_2014_Proband_RP-106, female, age 20 years at time of onset / first visual complaints, age 73 year at time of report, family origin not reported

CasePresentingHPOs: Nyctalopia HP:0000662, Constriction of peripheral visual field HP:0001133, Cataract HP:0000518, Attenuation of retinal blood vessels HP:0007843, Bone spicule pigmentation of the retina HP:0007737, Undetectable dark-adapted electroretinogram HP:0030474, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654

CaseHPOFreeText: The proband has been diagnosed with sporadic retinitis pigmentosa. Phenotypes included pale papillae in fundus.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband was not clearly described, but she was part of a cohort of patients with no previously-identified retinitis pigmentosa-associated variants.

CaseMethod1: SSCP analysis of 14 PCR-amplified PRPF4 exons

CaseMethod2: Sanger sequencing of PRPF4

CaseGenotypingMethod: Previous testing in the proband was not clearly described, but she was part of a cohort of patients with no previously-identified retinitis pigmentosa-associated variants. SSCP was performed on each of 14 PCR-amplified exons of PRPF4, followed by Sanger sequencing analysis.

Variant: The proband harbors the NM_001244926.2(PRPF4):c.572G>A (p.Arg191His) variant in the heterozygous state.

ClinVar ID: 967144

gnomAD: The NM_001244926.2(PRPF4):c.572G>A (p.Arg191His) variant is found in gnomAD v4.1.0 at a frequency of 0.00004999 (3 / 60014, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/9-113283400-G-A?dataset=gnomad_r4

VariantEvidence: NM_001244926.2(PRPF4):c.572G>A (p.Arg191His) is a missense variant. When overexpressed in zebrafish, the variant fails to rescue the lethality of Prpf4 silencing, unlike overexpression of the wild-type gene (Figure 2). Co-immunoprecipitation experiments show that the variant localizes normally but disrupts interaction with PRPF3 (Figure 3) and blocks PRPF4 integration into snRNP complexes (Figure 4).

CaseAddInfo: The proband has two daughters at ages 52 and 54 years who harbor the variant but showed no retinal abnormalities in ophthalmological examinations.

CasePMIDs: N/A

FamilyLabel: Hull_2016_Family_1

Family#PresentingHPOs: HP:0003581 (Adult onset), HP:0007663 (Reduced visual acuity), HP:0000533 (Chorioretinal atrophy)

Family#PresentingHPOFreeText: N/A

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

CountryOrigin: Irish ancestry

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Variants in REP1 and PRPH2 were initially excluded.

Family#Method1: Candidate gene sequencing

Family#Method2: Bidirectional, targeted Sanger sequencing within the RPE65 locus

Family#GenotypingMethod: Bidirectional Sanger sequencing of exon 13 of the RPE65 gene and flanking sequences

Affected: 2

Unaffected: 0

Segregations: 1 segregation was reported. The pedigree can be found in Figure 5. The possibility of family consanguinity was not mentioned.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Hull_2016_Patient_1.1

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

ClinVar: 750796

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

FamilyAddInfo: N/A

FamilyPMIDs: N/A

PMID: 27307694

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: Hull_2016_Family_2

Family#PresentingHPOs: HP:0003581 (Adult onset), HP:0007663 (Reduced visual acuity)

Family#PresentingHPOFreeText: N/A

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

CountryOrigin: Irish ancestry

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Variants in REP1 and PRPH2 were initially excluded.

Family#Method1: Candidate gene sequencing

Family#Method2: Bidirectional, targeted Sanger sequencing within the RPE65 locus

Family#GenotypingMethod: Bidirectional Sanger sequencing of exon 13 of the RPE65 gene and flanking sequences

Affected: 3

Unaffected: 2

Segregations: 3 segregations were reported. 1 inconsistent segregation was observed, with a genotype-positive individual who did not exhibit phenotypes. The pedigree can be found in Figure 5. The possibility of family consanguinity was not mentioned.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: 1 genotype-positive family member was phenotype-negative, but had an affected child.

ProbandLabel: Hull_2016_Patient_2.1

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

ClinVar: 750796

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

FamilyAddInfo: The possibility of family consanguinity was not mentioned.

FamilyPMIDs: N/A

ExperimentName: PDE6A forms a complex with PDE6B and PDE6G

InteractingGene: HGNC:8786 (PDE6B, implicated in retinitis pigmentosa 40) and HGNC:8789 (PDE6G, implicated in retinitis pigmentosa 57)

InteractionType: physical

InteractionMethod: size exclusion chromatography

InteractionEvidence: Purification of the cGMP phosphodiesterase complex from bovine rod outer segments yields a subunit of 88 kDa (PDE6A), a subunit of 84 kDa (PDE6B), and a subunit of 13 kDa (PDE6G), (Figure 2). This article shows that PDE6A interacts with and co-purifies with PDE6B and PDE6G in a single complex isolated from bovine retina. A subsequent article by Pittler et al. later established the position of PDE6A on chromosome 5 (PMID: 2155175).

ExperimentName: Intracellular localization of exogenously expressed wild-type and variant CLN5

NonPatientCell: BKH-21 cells (fibroblast-derived cell line, EFO:0002009)

GeneFunction: Localization to lysosome (GO:0005764)

GeneAlteration: The variant was introduced into the construct encoding CLN5 using site-directed mutagenesis.

FunctionalEvidence: Localization studies were performed in BHK-21 cells transiently transfected with wild-type or variant CLN5. The wild-type co-localized with lysosome and late endosome markers, while the variant co-localized with a Golgi marker (Fig. 3D–F) and showed some ER staining and vesicular-like staining. The stability of the variant following cyclohexamide treatment was also shorter than the wild-type. (Fig. 4G-4H).

FAVariants: The variant used was NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) (ClinVar:2564).

Case#: Holmberg_Patient_7, female, age 4 at onset and age 9 at time of study, Finnish origin with some ancestors traced to Sweden

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 4, while mental decline, visual deterioration and abolished ERG were found at age 7. Ataxia and Seizures developed at age 8, while Loss of independent walking and Giant flash visual evoked potentials occurred at age 9. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.

CaseNotHPOs: HP:0007082 (Dilated third ventricle)

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 a compound heterozygote harboring the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) and NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variants.

ClinVar: 2564, 56543

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant is 0.0008137 (within the European Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77575052-CAT-C The maximum allele frequency of the NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variant is 0.00007033 (within the European non-Finnish population, with no homozygotes) https://gnomad.broadinstitute.org/variant/13-77570218-A-AC

VariantEvidence: NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) is a recurring frameshift variant that is predicted to disrupt approximately 5% of CLN5 at the C-terminus and has been shown to disturb its localization to the lysosome (PMID:20052765). NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) is also a frameshift variant, is predicted to disrupt ~51% of the protein product, and exhibits defective localization to the ER rather than the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Holmberg_Patient_3, male, age 3 at onset and age 19 at time of death, 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 4, while mental decline, visual deterioration and abolished ERG were found at age 6. Giant flash visual evoked potentials were present at age 8, and ataxia at age 9. Seizures and Loss of independent walking occurred at age 10. 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.1028_1029del (p.Thr342_Tyr343insTer) variant.

ClinVar: 2564 (homozygous)

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

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

CaseAddInfo: N/A

CasePMIDs: N/A

PMID: 10953198

Gene: CLN5

HGNC: 2076

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

MONDO: 0009745

InheritancePattern: Autosomal Recessive

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

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

Case#: Zou_2017_Patient_F2-II:1, male, age 3 at time of report, family national origin reported to be from China

CasePresentingHPOs: HP:0000639 (Nystagmus), HP:0000613 (Photophobia), HP:0007663 (Reduced visual acuity), HP:0007750 (Hypoplasia of the fovea), HP:0007894 (Hypopigmentation of the fundus)

CaseHPOFreeText: The proband has been diagnosed with ocular albinism 1. Foveal hypoplasia was described as severe. Best-corrected visual acuity was limited to light perception.

CaseNotHPOs: HP:0007730 (Iris hypopigmentation)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing

CaseMethod2: N/A

CaseGenotypingMethod: Patients were genotyped by Sanger sequencing of PCR products from the 9 exons of the GPR143 gene.

Variant: The proband harbors the NM_000273.3(GPR143):c.276G>A (p.Trp92Ter) variant in the hemizygous state.

CAID: CA411999243

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

VariantEvidence: NM_000273.3(GPR143):c.276G>A (p.Trp92Ter) is a nonsense variant in exon 2 of 9, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 77% of the protein product.

CaseAddInfo: N/A

CasePMIDs: N/A

PMID: 28211458

Gene: GPR143

HGNC: 20145

Disease: X-linked recessive ocular albinism

MONDO: 0021019

InheritancePattern: X-linked recessive

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

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

Case#: Stunkel_2018_Patient_5, female, age 45 at diagnosis with congenital night blindness, at least as early as age 4 at time of onset, 52 years old at time of report, ethnic origin not mentioned

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000662 (Nyctalopia), HP:0000552 (Tritanomaly), HP:0000539 (Abnormality of refraction), HP:0001133 (Constriction of peripheral visual field), HP:0007737 (Bone spicule pigmentation of the retina), HP:0008043 (Retinal arteriolar constriction), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram),

CaseHPOFreeText: Refractive error was minimal. Progression of nyctalopia was noticed at 44 years of age. Rod-based ERG was not detectable at age 52.

CaseNotHPOs: HP:0030586 (Abnormal Ishihara plate test), HP:0000539 (Abnormality of refraction), HP:0000639 (Nystagmus), HP:0000486 (Strabismus), HP:0007663 (Reduced visual acuity), HP:0030473 (Abnormal light-adapted flicker electroretinogram), HP:0030617 (Abnormal OCT-measured foveal thickness)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Patient 5 was tested for known LCA-causing variants using an allele-specific method.

CaseMethod1: It is not clear whether Sanger sequencing was used to confirm the initial genotyping method.

CaseMethod2: N/A

CaseGenotypingMethod: Patient 5 was tested for known LCA-causing variants using an allele-specific method, leading to the detection of 2 variants in GUCY2D.

Variant: The individual is compound heterozygous for the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) and NM_000180.4(GUCY2D):c.2281C>T (p.p.Arg761Trp) variants.

ClinVar: 98563, 854601

gnomAD: The NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant exhibits a maximum allele frequency of 0.0002943 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7917236-C-T The NM_000180.4(GUCY2D):c.2281C>T (p.p.Arg761Trp) variant has a maximum allele frequency of 0.00004007 in gnomAD version 2.1.1 (in the African / African-American population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7917215-C-T

VariantEvidence: Evidence supporting the pathogenicity of the NM_000180.4(GUCY2D):c.2281C>T (p.p.Arg761Trp) variant is limited to computational prediction. Multiple publications have found functional defects in the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant. PMID: 25477517 shows defective binding to its interacting partner RD3, while PMID: 20050595 and PMID: 23035049 show reduced basal enzymatic activity and inability to interact with the activity-stimulating binding partner GCAP1.

CaseAddInfo: The possibility of consanguinity and variant phase have not been reported in detail.

CasePMIDs: N/A

FamilyLabel: Marlens_1997_Family_1

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

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

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Not specified

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: All RPE65 coding exons and flanking sequences were PCR-amplified and subjected to single-strand conformation analysis. Exon 10 was identified as a likely candidate to harbor a variant. All 14 exons of RPE65 were PCR-amplified and subjected to Sanger sequencing in both affected family members and their parents.

Family#GenotypingMethod: Screening of PCR products from affected and unaffected family members for the variants of interest was performed using SSCA for the maternal variant and AlwNI restriction digest for the paternal variant.

Affected: 2

Unaffected: 1

Segregations: The pedigree (Figure 1c) shows 1 segregation, with none inconsistent.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Marlhens_1997_Patient_III-2

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

ClinVar: 98821, 13114

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

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

FamilyPMIDs: N/A

Case#: 17-year-old boy, M, Age of Report: 17 y.o., Ethnicity: Indian/Pakistani descent.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0100832 (Vitreous floaters), HP:0030786 (Photopsia/ intermittent photopsia), HP:0007737 (Bone spicule pigmentation of the retina), HP:0001489 (Posterior vitreous detachment), HP:0030644 (Blind-spot enlargement),

CaseHPOFreeText: Proband came from a consanguineous family-multi-generational pedigree indicated his parents were first cousins of Indian/Pakistani descent.

A 17-year-old boy was referred for a history of pre- sumed pseudotumor cerebri associated with constricted visual fields. Prior to presenting at our clinic, he was observed to have retinal pigment and bilateral optic nerve edema. CT, MRI, and MRV were all normal. Lumbar puncture showed monocytes and lymphocytes but was otherwise normal. Given the lack of radiologic abnormalities and some recent weight gain, the diagnosis of pseudotumor cerebri was made and he was pre-scribed acetazolamide.

During the visit at our clinic, the patient reported a history of nyctalopia and some floaters in the right eye. He recalled, after starting the acetazolamide, some intermittent photopsia and visual obscurations. He was otherwise well and had lost 12 pounds over the last 2 months at the request of his doctor.

On our examination, best corrected visual acuity was 20/20–2 in each eye (−3.75 + 2.25 × 80 OD, −4.00 + 2.25 × 95 OS). Pupillary responses and eye movements were normal. Ishihara color plate testing was normal. Slit lamp examination and Goldmann applanation tonometry were normal. Fundus examination showed “bone spicule” pigmentary clumping scattered for 360 degrees in the mid periphery of each eye, internal limiting membrane irregularities over the macula, and a posterior vitreous detachment in the right eye (Figure 1a). The optic nerves were raised and irregular, consistent with optic nerve drusen (Figure 1b). There was no active edema or subretinal fluid.

OCT showed a distinct loss of photoreceptors outside the central macula. The subfoveal ellipsoid zone was also patchy in each eye (Figure 1c). Fundus autofluoresence (FAF) showed a hyperfluorescent ring within the macula and blocking of pigment beyond the macula (Figure 2a). Goldmann visual field testing showed an enlarged blind spot in each eye and generalized constriction of the isopters, in particular the I4e (Figure 2b). Multifocal electroretinogram (ERG) was severely abnormal with some central sparing. Full field ERG was isoelectric. B-scan ultra-sonography showed optic nerve drusen bilaterally (Figure 2c).

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Retinitis Pigmentosa Panel and My Retina Tracker Program Panel Plus.

Variant: NM_021831.6:c.1295A>T (p.Asp432Val).

ClinVar: N/A.

CAID: CA346180826.

gnomAD: Frequency: 6.800e-7. Link: https://gnomad.broadinstitute.org/variant/chr2-27056068-A-T?dataset=gnomad_r4.

VariantEvidence:N/A.

CaseAddInfo: Segregation analysis revealed that the unaffected mother and father were heterozygous for AGBL5: c.658C>T c.1295A>T, p. (Asp432Val).

CasePMIDs: N/A.

PMID: 15908424

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

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

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

Case#: Littink_2009_Family_Proband_II-1, male, onset in early childhood, age 12 years at time of report, family ancestry reported as Dutch

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity), HP:0000613 (Photophobia), HP:0000551 (Color vision defect)

CaseHPOFreeText: The proband and his sibling have a diagnosis of cone-rod dysfunction, including color vision described as severely abnormal and electroretinogram responses that showed absent cone a-wave but normal-to-subnormal rod function.

CaseNotHPOs: HP:0000662 (Nyctalopia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to homozygosity mapping of the sibling and his affected sister that identified a shared region of homozygosity on chromosome 13.

CaseMethod1: Homozygosity mapping

CaseMethod2: Sanger sequencing of CABP4

CaseGenotypingMethod: Genotyping began with homozygosity mapping of the sibling and his affected sister that identified a shared region of homozygosity on chromosome 13, followed by Sanger sequencing of PCR products from the CABP4 gene.

Variant: The individual harbors the NM_145200.5(CABP4):c.646C>T (p.Arg216Ter) variant in the homozygous state.

ClinVar ID: 190959

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.0001418 in the European (non-Finnish) population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/chr11-67457677-C-T?dataset=gnomad_r4

VariantEvidence: NM_145200.5(CABP4):c.646C>T (p.Arg216Ter) is a nonsense variant within exon 4 of 6 that is predicted to trigger nonsense-mediated decay.

CaseAddInfo: The proband's family includes a similarly affected sister harboring the variant in the homozygous state, and unaffected parents who each carry the variant in the heterozygous state. Consanguinity has not been commented upon.

CasePMIDs: N/A

FamilyLabel: Meunier_2016_Family_1

Family#PresentingHPOs: HP:0002097 (Emphysema), HP:0011510 (Drusen), HP:0011506 (Choroidal neovascularization), HP:0000529 (Progressive visual loss), HP:0032342 (Reduced forced expiratory volume in one second), HP:0033663 (Air trapping), HP:0033542 (Bronchial wall thickening), HP:0002110 (Bronchiectasis)

FamilyHPOFreeText: Early onset of abnormality in Bruch's membrane thickness. Drusen and choroidal neovascularization occurred between ages 23 and 40 (early onset) and were bilateral. Legal blindness was observed in almost all patients, although anti-VEGF treatment (bevacizumab) administration in one patient was associated with retained eye function. Pulmonary disease (severe emphysema) was late-onset. Patients in the 6th to 8th decades of life showed air trapping on CT scan, had reduced airflow (FEV1) by 28% to 73%, and bronchial abnormalities. Air trapping and hypoxia were detectable as early as the second decade of life and progressed to more severe pulmonary issues in older family members.

FamilyNotHPOs: HP:0025223 (Triggered by smoking), HP:0002099 (Asthma)

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: 7

Unaffected: 2

Segregations: 6

PublishedLOD: N/A

eLOD: 1.8

AddSegregationInfo: N/A

ProbandLabel: Meunier_2016_Family_1_patient_III-1

Variant: NM_000362.5(TIMP3):c.572A>G, p.Tyr191Cys is a missense variant predicted to introduce a new cysteine-encoding codon into exon 5.

ClinVar: 12677

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: While the family has not been previously described, the same variant has been published in PMID:7894485 (without reporting pulmonary symptoms).

PMID: 27601084

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

Case#: van_Huet_2014_Patient_A-II:1, female, age 8 years at the time of onset, age 59 at the time of report, national origin reported as Dutch

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0000545 (Myopia), HP:0000550 (Undetectable electroretinogram), HP:0007787 (Posterior subcapsular cataract), HP:0011504 (Bull's eye maculopathy), HP:0500087 (Peripapillary atrophy), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007722 (Retinal pigment epithelial atrophy), HP:0007737 (Bone spicule pigmentation of the retina)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

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

ClinVar: 3547

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

VariantEvidence: The NM_016247.4(IMPG2):c.887+430_908+274del variant is a deletion of exon 9 that is predicted to lead to in-frame removal of a region encoding 7 amino acids. When expressed exogenously in COS-1 cells, this results in retention of the protein product in the endoplasmic reticulum and failure to properly localize to the plasma membrane (PMID: 20673862, Figure 4).

CaseAddInfo: Despite the homozygous state of the variant, the family is reportedly not consanguineous. The proband has two affected siblings who share the same genotype, and each parent is a heterozygous carrier.

CasePMIDs: PMID: 20673862

FamilyLabel: van_Huet_2014_Family_B, ethnic origin reported as Iraqi Jewish

Family#PresentingHPOs: HP:0011463 (Childhood onset), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0007787 (Posterior subcapsular cataract), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007722 (Retinal pigment epithelial atrophy), HP:0007737 (Bone spicule pigmentation of the retina)

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

Family#PresentingNotHPOs: N/A

CountryOrigin: Iraq

Ethnicity: Reported as Iraqi Jewish

Race: Not mentioned

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

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

Family#Method2: N/A

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

Affected: 3

Unaffected: 0

Segregations: Two segregations are reported in the family, with none inconsistent. The family is apparently consanguineous, with the parents being first cousins. The pedigree is shown in Figure 1.

PublishedLOD: N/A

eLOD: 1.20

AddSegregationInfo: N/A

ProbandLabel: van_Huet_2014_Patient_B-II:1

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

ClinVar: 3546

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

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

FamilyPMIDs: N/A

PMID: 24876279

Gene: IMPG2

HGNC: 18362

Disease: retinitis pigmentosa 56

MONDO: 0013314

InheritancePattern: semi-dominant

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

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

PMID: 36342076

2 patients (fetuses) with recurrent autosomal dominant RBP4 variant

PMID: 19409519

Gene: ADAM9

HGNC: 216

Disease: cone-rod dystrophy 9

MONDO: MONDO:0013002

InheritancePattern: autosomal recessive

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

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

ExperimentName: Mouse model of Adam9 loss-of-function

NonHumanModel: Mus musculus

GeneAlteration: The mice harbor homozygous knockout of the Adam9 gene by an insertion of a neomycin selection cassette in to the exon encoding amino acids 32 to 66 of Adam9 (PMID: 11839819).

ModelPhenotype: HP:0000546 (Retinal degeneration), HP:0007703 (Abnormality of retinal pigmentation), HP:0030610 (Photoreceptor outer segment loss on macular OCT), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0007984 (Electronegative electroretinogram), HP:0008323 (Abnormal light- and dark-adapted electroretinogram)

HumanPhenotype: 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), HP:0000548 (Cone/cone-rod dystrophy), HP:0007994 (Peripheral visual field loss), HP:0000545 (Myopia)

ModelEvidence: The affected mice exhibit an abnormal gap between the RPE and the photoreceptor outer segment, which would normally be in contact (Figure 5B). The gap contains macrophages (Figure 5L). Outer nuclear layer thinning is observed (Figure 5D), as well as material deposited between the RPE and Bruch's membrane, which may be analogous to drusen deposits in humans (Figure 5K). These findings collectively show an adhesion defect at the interface between the photoreceptor outer segment and the RPE. This evidence of retinal degeneration was complemented by abnormalities in both rod- and cone-driven ERG responses (Figure 4), matching a feature of the human patients.

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

PMID: 11427722

Gene: PRPH2

HGNC: 9942

Disease: retinitis pigmentosa 7

MONDO: 0011974

InheritancePattern: semi-dominant

Prevalence: The incidence of PRPH2-related cases among inherited retinal dystrophies is reported to range from 3.5% in North America to 10.3% in France (PMID: 36010202).

Penetrance: The penetrance among biallelic cases appears to be complete, while the monoallelic cases exhibit incomplete penetrance (PMID: 36609934).

ExperimentName: Prph2 interacts with Rom1

InteractingGene: ROM1 (HGNC:10254)

InteractionType: Physical

InteractionMethod: Co-immunoprecipitation

InteractionEvidence: Immunoprecipitation of endogenous Prph2 from mouse retinal extracts pulled down Rom1, and vice versa (Fig. 6C).

PMID: 25001182

Gene: PRPH2

HGNC: 9942

Disease: retinitis pigmentosa 7

MONDO: 0011974

InheritancePattern: semi-dominant

Prevalence: The incidence of PRPH2-related cases among inherited retinal dystrophies is reported to range from 3.5% in North America to 10.3% in France (PMID: 36010202).

Penetrance: The penetrance among biallelic cases appears to be complete, while the monoallelic cases exhibit incomplete penetrance (PMID: 36609934).

ExperimentName: Knockin of the p.Tyr141Cys variant into mouse Prph2 results in retinal defects.

NonHumanModel: Mus musculus

GeneAlteration: The model animals are heterozygous for knock-in of the p.Tyr141Cys variant into the Prph2 locus.

ModelPhenotype: HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0000546 (Retinal degeneration), HP:0030610 (Photoreceptor outer segment loss on macular OCT), HP:0012045 (Retinal flecks)

HumanPhenotype: HP:0030643 (Vitelliform-like retinal lesions), HP:0000533 (Chorioretinal atrophy), HP:0001105 (Retinal atrophy), HP:0007663 (Reduced visual acuity), HP:0000580 (Pigmentary retinopathy), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram), HP:0007843 (Attenuation of retinal blood vessels), HP:0011506 (Choroidal neovascularization), HP:0030499 (Macular drusen)

ModelEvidence: This knock-in mouse model has normal expression and localization of Prph2 (Fig. 1), but exhibits phenotypes including photoreceptor outer segment loss (Fig. 2), decreased rod ERG (Fig. 3A), and photoreceptor layer degeneration (Fig. 4). Homozygous mice showed decreased cone ERG as well (Figs. 3B, 3C). Yellow retinal flecks were observed in the fundus (Fig. 5). Abnormal high molecular weight complexes containing Prph2 were also observed in western blotting, along with the absence of normal monomers and dimers in the homozygous animals (Figs. 6 and 7).

ModelVariant: This mouse model has introduced a disease-associated variant known from an affected human patient, NM_000322.5(PRPH2):c.422A>G (p.Tyr141Cys), ClinVar ID: 98666.

PMID: 9662406

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: 12160730

Gene: RPGR

HGNC: 10295

Disease: RPGR-related retinopathy

MONDO: MONDO:0100437

InheritancePattern: X-linked

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

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

PMID: 19183411

Gene: TOPORS

Case#: Patient 5, male, 16 years (at report)

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

CaseHPOsFreeText: Poor vision and photophobia since the age of 4. BCVA was 0.4 LogMAR in right eye and 0.52 LogMAR in left eye with a refractive error of −5.75 sph −3.00 cyl/15° D in right eye and of −6.00 sph −3.50 cyl/170° D in left eye. Fundus exam showed normal optic disk, a loss of the foveal reflex, and peripheral RPE mottling. Fundus autofluorescence revealed a central hypofluorescence with a mild perifoveal hyperfluorescent area in both eyes while OCT imaging showed a foveal photoreceptor disruption associated with a normal central macular thickness and relative sparing of paracentral retina (Figure 6). Flash full-field ERG recordings showed reduced responses mostly for the photopic component. Visual fields display a central scotoma.

CaseNotHPOs:

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

CaseMethod1: NGS panel

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

Variant: Variant 1) c.409C>T (p.Arg137Ter)(paternal) Variant 2) c.77C>A (p.Thr26Asn)(maternal)

ClinVar: Variant 1) 60755; Variant 2) N/A

CAID: Variant 1) CA144657; Variant 2) CA356375011

gnomAD: Variant 1) 0.00001764 (European non-Finnish). No homozygotes in any population. Variant 2) Not in gnomAD

VariantEvidence: Variant 1) no nonsense-mediated decay of mRNA was previously reported (Roosing et al, 2013). In the current paper, structural analysis showed that truncation would delete the α4, β6, and α5 structural elements. The lack of β6 and α5 would most likely prevent the correct α/β fold from forming, affecting the guanine nucleotide binding pocket, and resulting in protein degradation. Variant 2) Molecular dynamics simulations of p.Thr26Asn in both its active and inactive states revealed an allosteric structural mechanism that impairs the binding of Mg2+, thus decreasing the affinity for GTP. The impaired GTP-GDP exchange ultimately locks Rab-28 in a GDP-bound inactive state.

CaseAddInfo: Parents and brother are clinically unaffected. The father and brother are heterozygous for the nonsense variant and the mother is heterozygous for the missense variant.

Case#: Patient 4, 64 years (at report), female

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

CaseHPOsFreeText: Relatively late onset of disease (first symptoms around age 30 years). 1.7 LogMAR in both eyes. Refractive error was −2.00 sph in both eyes. Fundus exam showed a tigroid aspect with vessel thinning, macular atrophy, and optic pallor. Flash full-field ERG recordings showed a non-detectable response for the photopic component and a reduced response for the scotopic response. MfERG response was markedly reduced but still detectable in both eyes, presenting a residual foveal cone function. OCT macular scan showed a marked foveal thinning with advanced photo-receptor layer disruption (Fig 5)

CaseNotHPOs:

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

CaseMethod1: NGS panel

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

Variant: c.321G>A (p.Trp107Ter), homozygous

ClinVar: N/A

CAID: CA356373812

gnomAD: The variant is absent in gnomAD.

VariantEvidence: Structural analysis of p.Trp107Ter suggested that truncation of the protein sequence after residue W107 would break up helix α3, resulting in the absence of the C-terminal part of α3, β5, α4, β6, and α5. Missing structural elements β5, β6, and α5 would most probably result in failure to fold correctly or bind GTP/GDP causing degradation.

Case#: Qin_2005_Patient_7, gender not reported, age 1 year at report, national origin reported as Japanese

CasePresentingHPOs: HP:0004349 (Reduced bone mineral density), HP:0008052 (Retinal fold), HP:0000541 (Retinal detachment)

CaseHPOFreeText: The patient has been diagnosed with FEVR. Retinal folds and later complete retinal detachment were present in both eyes.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping appears to have been limited to the LRP5 and FZD4 loci.

CaseMethod1: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 and FZD4 loci

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 and FZD4 loci.

Variant: The patient harbors the NM_002335.4(LRP5):c.1604C>T (p.Thr535Met) and NM_002335.4(LRP5):c.1850T>G (p.Phe617Cys) variants in the compound heterozygous state.

ClinVar: 2137179

CAID: CA224268235

gnomAD: The NM_002335.4(LRP5):c.1850T>G (p.Phe617Cys) variant was not found in gnomAD v2.1.1. The NM_002335.4(LRP5):c.1604C>T (p.Thr535Met) variant was found in gnomAD v2.1.1 at a frequency of 0.00001759 (2/113686) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-68170970-C-T?dataset=gnomad_r2_1

VariantEvidence: NM_002335.4(LRP5):c.1604C>T (p.Thr535Met) and NM_002335.4(LRP5):c.1850T>G (p.Phe617Cys) are missense variants in exons 8 and 9, respectively, out of 23. Neither has evidence of an impact on the gene product.

CaseAddInfo: The proband's parents are carriers for p.Phe617Cys (maternal) and p.Thr535Met (paternal). The father was apparently unaffected in terms of retinal change and reduced bone mass. The mother was subclinically affected unilaterally with localized retinal avascularization with tortuosity of the retinal vessels and reduced bone density.

CasePMIDs: N/A

Case#: Qin_2005_patient_8, female, age 14 years at report, national origin reported as Japanese

CasePresentingHPOs: HP:0001103 (Abnormal macular morphology), HP:0004349 (Reduced bone mineral density), HP:0003621 (Juvenile onset)

CaseHPOFreeText: The patient has been diagnosed with simplex FEVR, with bilateral dragged macula.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping appears to have been limited to the LRP5 and FZD4 loci.

CaseMethod1: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 and FZD4 loci

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 and FZD4 loci.

Variant: The patient harbors the NM_002335.4(LRP5):c.804_813del (p.Gly269fs) and NM_002335.4(LRP5):c.1828G>A (p.Gly610Arg) variants in the compound heterozygous state.

ClinVar: 6295, 6294

gnomAD: The NM_002335.4(LRP5):c.804_813del (p.Gly269fs) variant was not found in gnomAD v2.1.1. The NM_002335.4(LRP5):c.1828G>A (p.Gly610Arg) variant was found in gnomAD v2.1.1 at a frequency of 0.00002644 (3/113484) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-68174018-G-A

VariantEvidence: NM_002335.4(LRP5):c.1828G>A (p.Gly610Arg) is a missense variant in exon 9 that does not have experimental evidence of an impact on the protein product. NM_002335.4(LRP5):c.804_813del (p.Gly269fs) is a frameshift variant in exon 4 of 23 that is predicted to trigger nonsense-mediated decay or to at least disrupt the C-terminal 83% of the protein product.

CaseAddInfo: The patient has no family history of FEVR in her parents and brother, although bone mineral density was reduced in both parents. The mother is a carrier for p.Gly610Arg, while the father and brother are heterozygous for p.G268fsX272.

CasePMIDs: N/A

Case#: Perrault_2000_Family_3_Proband, Female, age unknown, family origin in Tunisia with Jewish Sefardi 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:c.389del (p.Pro130LeufsTer36) variant.

ClinVar: 98602

gnomAD: The variant exhibits a maximum allele frequency of 0.00008370 in gnomAD version 2.1.1 (in the Latino / Admixed American population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7906751-AC-A

VariantEvidence: The NM_000180.4:c.389del (p.Pro130LeufsTer36) variant is predicted to trigger nonsense mediated decay or to disrupt ~88% of the protein product by frameshift.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 7581387, PMID: 8641699

FamilyLabel: Perrault_2000_Family_11

Family#PresentingHPOs: N/A

Family#PresentingHPOFreeText: Affected family members are described as having Leber congenital amaurosis.

FamilyNotHPOs: N/A

CountryOrigin: Algeria

Ethnicity: Arab

Race: Not described

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

Family#Method1: Sanger sequencing of PCR products from each of the 20 exons

Family#Method2: N/A

Family#GenotypingMethod: Family members were initially subjected to 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.

Affected: 4

Unaffected: 0

Segregations: 3 segregations were reported, with none inconsistent with the proposed mechanism of inheritance (Figure 3a). The family is reportedly consanguineous.

PublishedLOD: N/A

eLOD: 1.81

AddSegregationInfo: N/A

ProbandLabel: Perrault_2000_Family_11_Proband

Variant: Affected individuals are 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

FamilyAddInfo: N/A

FamilyPMIDs: PMID: 7581387, PMID: 8641699