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.

FamilyLabel: van_Huet_2014_Family_A, national origin reported as Dutch

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

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

Family#PresentingNotHPOs: N/A

CountryOrigin: Netherlands

Ethnicity: Reported as Dutch

Race: Not mentioned

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

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

Family#Method2: N/A

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

Affected: 3

Unaffected: 3

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

PublishedLOD: N/A

eLOD: 1.50

AddSegregationInfo: N/A

ProbandLabel: van_Huet_2014_Patient_A-II:1

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

ClinVar: 3547

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

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

FamilyPMIDs: N/A

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

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

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

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

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

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

ClinVar: 437938

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

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

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

CasePMIDs: PMID: 20673862

PMID: 27587748

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#: Ebenezer_2005_Family_B_Patient_IV:11, male, age 44, family origin reported to be British

CasePresentingHPOs: HP:0003581 (Adult onset), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0000613 (Photophobia), HP:0000545 (Myopia), HP:0000483 (Astigmatism), HP:0007803 (Monochromacy), HP:0007722 (Retinal pigment epithelial atrophy), HP:0025159 (Hypoautofluorescent retinal lesion), HP:0007814 (Retinal pigment epithelial mottling)

CaseHPOFreeText: The proband has been diagnosed with progressive retinal degeneration / cone-rod dystrophy, with the family exhibiting an X-linked pattern of inheritance.

CaseNotHPOs: HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing of exon 15 of RPGR

CaseMethod2: N/A

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

Variant: The proband harbors the NM_001034853.2(RPGR):c.2929G>T (p.Gly977Ter) variant in the hemizygous state.

ClinVar: 9918

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

VariantEvidence: NM_001034853.2(RPGR):c.2929G>T (p.Gly977Ter) is a nonsense variant in the final exon (exon 15) that is not predicted to trigger nonsense-mediated decay, but disrupts ~15% of the C-terminus of the protein product.

CaseAddInfo: The proband is a member of Family B (shown in Figure 1), which includes four other affected genotype-positive males and as well as four carrier females who showed reduced visual acuity and golden tapetal reflex.

CasePMIDs: N/A

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

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

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

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

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing of exon 15 of RPGR

CaseMethod2: N/A

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

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

ClinVar: 9917

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

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

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

CasePMIDs: N/A

PMID: 25185585

Gene: GPR143

HGNC: 20145

Disease: X-linked recessive ocular albinism

MONDO: 0021019

InheritancePattern: X-linked recessive

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

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

PMID: 16505055

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#: Yzer_2006_Patient_21067, female, age 6 months at diagnosis, family origin not described

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0000486 (Strabismus), HP:0000565 (Esotropia), HP:0008043 (Retinal arteriolar constriction), HP:0000543 (Optic disc pallor), HP:0012426 (Optic disc drusen), HP:0012643 (Foveal hypopigmentation), HP:0007703 (Abnormality of retinal pigmentation), HP:0000639 (Nystagmus), HP:0000613 (Photophobia), HP:0007663 (Reduced visual acuity), HP:0000550 (Undetectable electroretinogram)

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

CaseNotHPOs: HP:0000662 (Nyctalopia), HP:0000563 (Keratoconus)

CaseNotHPOFreeText: Fundus was described as largely normal.

CasePreviousTesting: An LCA-specific microarray ChIP was used for initial genotyping, using antisense oligos to screen for 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK).

CaseMethod1: Sanger sequencing of PCR products from each of the 20 exons of GUCY2D.

CaseMethod2: N/A

CaseGenotypingMethod: The individual was initially screened using an LCA-specific microarray ChIP with antisense oligos to detect 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK). Subsequent genotyping was performed by Sanger sequencing of PCR products from all 20 exons of the GUCY2D locus.

Variant: The individual is compound heterozygous for the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) and NM_000180.4(GUCY2D):c.2837C>T (p.Ala946Val) variants.

ClinVar: 98563, 98576

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.2837C>T (p.Ala946Val) variant exhibits a maximum allele frequency of 0.00004013 in gnomAD version 2.1.1 (in the African / African-American population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7918713-C-T

VariantEvidence: 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. Evidence for the pathogenicity of the NM_000180.4(GUCY2D):c.2837C>T (p.Ala946Val) variant is limited to computational predictions.

CaseAddInfo: Parents were reported to be consanguineous. Segregation / phasing of two variants was confirmed by parental genotyping.

CasePMIDs: N/A

ExperimentName: Variant knock-in to the mouse Rpe65 locus triggers aberrant mRNA splicing.

NonHumanModel: Mus musculus

GeneAlteration: A substitution equivalent to the human NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was knocked into the mouse Rpe65 locus by CRISPR/Cas9-based editing.

ModelPhenotype: HP:0000479 (Abnormal retinal morphology), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), Retinal thinning HP:0030329

HumanPhenotype: HP:0000662 (Nyctalopia), HP:0007688 (Undetectable light- and dark-adapted electroretinogram), HP:0001098 (Abnormal fundus morphology), HP:0000529 (Progressive visual loss)

ModelEvidence: Despite normal 11-cis retinal levels (Figure 3E), the heterozygous knock-in animals exhibit abnormal accumulation of retinyl esters (Figure 3F), recapitulating a key molecular defect of the human patients. The homozygous (but not heterozygous) knock-in animals also exhibit vacuole formation in the outer segment adjacent to the retinal pigment epithelium (Figure 3B) and abnormalities on dark-adapted ERG indicative of slower recovery of rod function (Figures 4A, 4B) and cone function (Figure 5D) as well as reduced retinal thickness (Figure 5A) after long-term chronic visual pigment bleaching.

ModelVariant: The model knocks the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant (ClinVar:750796) into the mouse Rpe65 locus.

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: 23993198

Gene: IMPG1

HGNC: 6055

Disease: vitelliform macular dystrophy 4

MONDO: 0014508

InheritancePattern: semi-dominant

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

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

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

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

ClinVar: 162134

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

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

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

CasePMIDs: N/A

Selection B- Gene function is consistent with phenotype.

ExperimentName: RP1L1 protein localizes to the axoneme of the outer segment of rod photoreceptor cells, but not to the connecting cilium, inner segment, or basal bodies (and from cone cells altogether).

GOterm: GO:0120200 (rod photoreceptor outer segment)

FunctionalEvidence: Immunofluorescent staining of Rp1l1 was performed in retinal sections, with staining of rhodopsin, Rp1, and gamma-tubulin for comparison (Figures 1E, 2A, 2B, 2C).

FunctionalHPO: Macular dystrophy HP:0007754, Reduced visual acuity HP:0007663

PMID: 19657028

Gene: RP1L1

HGNC: 15946

Disease: occult macular dystrophy

MONDO: 0013316

InheritancePattern: autosomal dominant

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

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

FamilyLabel: Weber_1994_Family_B

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

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

FamilyNotHPOs: N/A

CountryOrigin: Canada (PMID:7920634), genealogy indicating Irish descent (PMID: 2695876)

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

Family#GenotypingMethod: Sanger sequencing of Weber_1994_Family_B_patient_V-1

Affected: 1

Unaffected: 1

Segregations: N/A

PublishedLOD: A multipoint LOD Score of 7.43 was published for the interval between tandem repeat markers D22S275 and D22S274 on chromosome 22q13, a region that includes the TIMP3 locus (PMID:7920634).

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Weber_1994_Family_B_patient_V-1

Variant: The variant is NM_000362.5(TIMP3):c.610A>T, p.Ser204Cys

ClinVar: 12676

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: Variant was first referred to in PMID:7894485 as "Ser181Cys" but encodes Ser204Cys in the updated polypeptide sequence. A more detailed pedigree is available from an earlier publication (PMID:7920634), but genotyping was not performed at that time, resulting in a lack of segregation data.

FamilyPMIDs: PMID:2695876, PMID:7920634

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

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo:

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

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

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

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

GenotypingMethod: Sanger sequencing

PreviouslyPublished: PMID:2695876, PMID:7920634

SupplementalData: N/A

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

ClinVar: 12676

gnomAD: Variant is absent from gnomAD.

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

PMID: 31757977

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

Case#: Georgiou_2024_Family_JP01_Proband_P12, male, reported at age 6 years, family origin reported as from Japan

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

CaseHPOFreeText: BCVA began at 0.20 logMAR and progressed to 0.57 logMAR.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel / WES / WGS

CaseMethod2: Sanger sequencing of RBP3

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

Variant: The individual harbors the NM_002900.3(RBP3):c.632G>A (p.Trp211Ter) and NM_002900.3(RBP3):c.345_349del (p.Trp116AlafsTer7) variants in the compound heterozygous state.

ClinVar ID: 838965

CAID CA2953902720

gnomAD: The NM_002900.3(RBP3):c.345_349del (p.Trp116AlafsTer7) variant was not found in gnomAD version 4.1.1. The NM_002900.3(RBP3):c.632G>A (p.Trp211Ter) variant is found in gnomAD version 4.1.1 at a frequency of 0.00008913 (4 / 44878) in the East Asian population https://gnomad.broadinstitute.org/variant/chr10-47349116-G-A?dataset=gnomad_r4

VariantEvidence: NM_002900.3(RBP3):c.632G>A (p.Trp211Ter) is a nonsense variant within exon 1 of 4 that is predicted to trigger nonsense-mediated decay. NM_002900.3(RBP3):c.345_349del (p.Trp116AlafsTer7) is a frameshift variant within exon 1 of 4 that is predicted to trigger nonsense-mediated decay.

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel / WES / WGS

CaseMethod2: Sanger sequencing of RBP3

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

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

ClinVar ID: 1069291

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

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

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

CasePMIDs: N/A

Case

PMID: 18836446

Gene: EYS

HGNC: 21555

Disease: Retinitis pigmentosa 25

MONDO: MONDO:0011272

InheritancePattern: autosomal recessive

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

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

PMID: 36317196

PMID: 19615668

Gene: PDE6C

HGNC: 8787

Disease: cone dystrophy 4

MONDO: 0013129

InheritancePattern: recessive

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

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

PMID: 25515582

Gene: GUCY2D

HGNC: 4689

Disease: Cone-rod dystrophy 6

MONDO: 0011143

InheritancePattern: Autosomal Dominant

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

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

Case#: Meindl_1996_Family_F50_Proband, male, age not specified, family origin either German or British

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: Sanger sequencing of the RPGR locus

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

Variant: The affected family members harbor the NM_001034853.2(RPGR):c.581G>A (p.Trp194Ter) variant in the hemizygous state.

ClinVar: 98790

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

VariantEvidence: NM_001034853.2(RPGR):c.581G>A (p.Trp194Ter) is a nonsense variant predicted to trigger nonsense-mediated decay or to at least disrupt the C-terminal 76% of the protein product.

CaseAddInfo: The proband is a member of Family F50.

CasePMIDs: N/A

PMID: 8673101

Gene: RPGR

HGNC: 10295

Disease: RPGR-related retinopathy

MONDO: MONDO:0100437

InheritancePattern: X-linked

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

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

PMID: 30080950

Gene: PDE6C

HGNC: 8787

Disease: cone dystrophy 4

MONDO: 0013129

InheritancePattern: recessive

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

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

Case#: Gupta_2021_Proband_1, female, age 25 years at time of report, ethnic origin not reported

CasePresentingHPOs: HP:0000575 (Scotoma), HP:0007663 (Reduced visual acuity), HP:0030500 (Yellow/white lesions of the macula, specifically small foveal yellow spots), HP:0030627 (Foveal hyporeflective spaces on macular OCT), HP:0008323 (Abnormal light- and dark-adapted electroretinogram, specifically reduced response in the center of one retina)

CaseHPOFreeText: The patient has been diagnosed with foveomacular vitelliform dystrophy with adult onset.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing appears to have included genotyping of the

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: Genotyping appears to have included

Variant: The proband harbors the NM_001563.4(IMPG1):c.461T>C (p.Leu154Pro) variant in the heterozygous state.

ClinVar: 162136

gnomAD: This variant was found in gnomAD v2.1.1 at a frequency of 0.00007924 (9/113576) in the European non-Finnish population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76744345-A-G

VariantEvidence: NM_001563.4(IMPG1):c.461T>C (p.Leu154Pro) is a missense variant that does not have evidence confirming an impact on the gene product. However, another study has reported apparently unrelated affected patients harboring this variant in the compound heterozygous state (PMID: 23993198), in trans with the NM_001563.4(IMPG1):c.1519C>T (p.Arg507Ter) variant.

CaseAddInfo: The variant is paternally inherited in this case, and the patient's father has been diagnosed with central serous chorioretinopathy but lacks other features of vitelliform macular dystrophy. This indicates that central serous chorioretinopathy is part of the spectrum of monoallelic disease.

CasePMIDs: N/A

PMID: 32323592

PMID: 17255100

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

Zebrafish harboring an engineered mutation in the prpf4 gene exhibit enhanced brain and spinal cord apoptosis. The mechanism is loss-of-function. Matches the patients?

PMID: 20826268

Gene: RP1L1

HGNC: 15946

Disease: occult macular dystrophy

MONDO: 0013316

InheritancePattern: autosomal dominant

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

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

Case#: 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

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.

ExperimentName: Phenotypes from homozygous Gucy2e mouse knockout model

NonHumanModel: Mus musculus

GeneAlteration: The mouse Gucy2e gene was disrupted by the introduction of a neomycin-resistance gene cassette into exon 5, resulting in a truncated protein lacking its transmembrane domain (PMID: 10407028). The effects of this knockout were studied in both heterozygous and homozygous states.

ModelPhenotype: HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0030465 (Undetectable light-adapted electroretinogram), HP:0008020 (Cone dystrophy)

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

ModelEvidence: By 5 weeks of age, Gucy2e-deficient animals exhibit dramatic reduction/degeneration of cones in the outer nuclear layer (Fig. 3a–d). This was confirmed by disappearance of labeling of cone cell nuclei by the lectin PNA (Fig. 3g-h). ERG showed that rod a-wave and b-wave were markedly reduced by 1 month of age, while cone responses were nondetectable as early as 2 months of age (Fig. 4a-b). A proposed explanation for the absence of more severe rod defects is the continued presence of the Gucy2f paralog in this mouse model, which may compensate for the absence of Gucy2e function in rod cells specifically. This hypothesis has been confirmed in a subsequent double-knockout model (PMID: 17255100)

ModelVariant: The mouse model disrupts the expression of the endogenous GC1 protein product but does not feature knock-in of a variant from a human patient.

PMID: 10407028

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

PMID: 24009529

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#: Harville_2010_Patient_A2885–II2, sex and age not reported, family origin reportedly from Saudi Arabia

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy), HP:0010442 (Polydactyly), HP:0001513 (Obesity), HP:0000077 (Abnormality of the kidney), HP:0001249 (Intellectual disability), HP:0004322 (Short stature), HP:0001263 (Global developmental delay), HP:0000823 (Delayed puberty)

CaseHPOFreeText: The proband has an initial clinical diagnosis of Bardet-Biedl syndrome.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was initially subjected to homozygosity mapping to identify parts of the genome to search for the basis of recessive disease.

CaseMethod1: homozygosity mapping

CaseMethod2: Sanger sequencing of the exons of any of the 14 BBS-associated loci (BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, and CEP290) that showed homozygosity.

CaseGenotypingMethod: The proband was initially subjected to homozygosity mapping to identify parts of the genome to search for the basis of recessive disease. This was followed by Sanger sequencing of the exons of any of the 14 BBS-associated loci (BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, and CEP290) that showed homozygosity.

Variant: The proband harbors the NM_024649.5(BBS1):c.124+1G>A variant in the homozygous state.

ClinVar ID: 557428

gnomAD: The NM_024649.5(BBS1):c.124+1G>A variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_024649.5(BBS1):c.124+1G>A is a canonical splice site variant in intron 2 that is predicted but not confirmed to disrupt BBS1 splicing.

CaseAddInfo: The proband's family is reportedly consanguineous and includes a similarly affected sibling sharing the same homozygous genotype.

CasePMIDs: N/A

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

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

GeneAlteration: TIMP3 expression constructs encoding the "Ser181Cys", "Ser156Cys", "Gly166Cys", and "Glu139X" variants (officially referred to as the Ser204Cys, Ser179Cys, Gly189Cys, and Glu162X variants) were generated by PCR-based mutagenesis of the wild-type TIMP-3-pCI.neo construct.

FunctionalEvidence: The TIMP3 variants were exogenously expressed in COS-7 cells alongside the wild-type control. Reverse zymography of extracellular matrix from these cells revealed the presence of dimeric species with metalloproteinase inhibitory activity in the variant-transfected conditions, but not in the wild-type control (Figure 3). These bands were confirmed to be TIMP3 by immunoblotting the extracellular matrix from these cells under non-reducing conditions, as they disappeared under reducing conditions (Figure 4). Under reducing conditions, the variant-transfected cells show higher levels of monomeric TIMP3 relative to the wild-type control (Figure 4b), but it should be noted that the wild-type control is depicted on a separate blot / exposure. The dimerized Glu162X variant is difficult to distinguish from other full-length monomeric species, but appears to be present as well (Figure 5).

FAVariants: Variants used were equivalent to NM_000362.5(TIMP3):c.610A>T (p.Ser204Cys) (ClinVarID:12676), NM_000362.5(TIMP3):c.536C>G, (p.Ser179Cys) (ClinVarID:12678), NM_000362.5(TIMP3):c.565G>T (p.Gly189Cys) (ClinVarID:12679), and NM_000362.5(TIMP3):c.484G>T (p.Glu162X) (ClinVarID:12680).

PMID: 37264419

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

InheritancePattern: autosomal dominant

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

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

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: whole exome sequencing

CaseMethod2: Sanger sequencing of the coding regions of PRPF4

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

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

ClinVar ID: 1395419

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

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

CaseAddInfo: The proband has apparently unaffected parents.

CasePMIDs: N/A

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: 12920075

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: 20052765

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: 26298565

Gene: GUCY2D

HGNC: 4689

Disease: Cone-rod dystrophy 6

MONDO: 0011143

InheritancePattern: Autosomal Dominant

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

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

Case#: Jiang_2015_Patient_010097, female, age 4 at time of report, national origin listed as Chinese

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0025573 (Mild myopia), HP:0007663 (Reduced visual acuity), HP:0030329 (Retinal thinning), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0007401 (Macular atrophy)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000662 (Nyctalopia), HP:0000639 (Nystagmus), HP:0000551 (Color vision defect)

CaseNotHPOFreeText: N/A

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

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

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

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

Variant: The proband harbors the NM_000180.4(GUCY2D):c.2513G>C (p.Arg838Pro) variant in the heterozygous state.

ClinVar: 811743

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.4(GUCY2D):c.2513G>C (p.Arg838Pro) is a missense variant located within the coiled-coil domain that mediates dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565). The variant has been reported in an apparently unrelated family from this same publication.

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

CasePMIDs: N/A

PMID: 29777959

Gene: IMPG1

HGNC: 6055

Disease: vitelliform macular dystrophy 4

MONDO: 0014508

InheritancePattern: semi-dominant

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

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

PMID: 11734514

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: 17065522

GeneName: GNAT2

HGNC: 4394

Disease: achromatopsia 4

MonDO ID: MONDO_0013465

Inheritance: autosomal recessive

This article studies mice known as rds with homozygous disruption of the Prph2 locus. Phenotypes include progressive degeneration of retina, absence of rods at age 7-10 months, and reduction of the number of rows of photosensitive cell nuclei to only 1-4 rows. The mouse has been previously published (PMID: 705766).

Case#: Lebrun_2009_Patient_2, male, age 2-3 at onset, age 15 at death, family ethnicity reported as Afghan

CasePresentingHPOs: HP:0001251 (Ataxia), HP:0002474 (Expressive language delay), HP:0001250 (Seizure), HP:0011463 (Childhood onset), HP:0011421 (Death in adolescence)

CaseHPOFreeText: Onset was at age 2-3, with the first presenting phenotypes being ataxia and delay in speech development. Seizures began at age 4. Death occurred at age 15.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The extent of previous testing within this patient is unclear.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: CLN5 mRNA was reverse transcribed, PCR-amplified, and subjected to Sanger sequencing. This process was performed for both affected and control individuals (parents).

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.990G>T (p.Trp330Cys) variant, (although this variant is referred to in the article as c.1137G>T (p.Trp379Cys)).

ClinVar: 56530

gnomAD: The variant is reported to have a maximum allele frequency of 0.00006484 (in the European non-Finnish population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77575017-G-T

VariantEvidence: The missense variant introduces an additional cysteine into the protein product, potentially disrupting folding and three-dimensional structure. Immunofluorescent detection of the exogenously expressed variant in COS7 cells shows aberrant localization to the ER in contrast to the wild-type localization to the lysosome (Figure 3).

CaseAddInfo: The patient's family is consanguineous, as parents are described as first degree cousins. Parents were heterozygous for the variant. Family relationships between individuals were verified.

CasePMIDs: N/A

Case#: Lebrun_2009_Patient_1, male, age 5 at onset, U.K. origin with family ethnicity reported as Pakistani

CasePresentingHPOs: HP:0007010 (Poor fine motor coordination), HP:0007015 (Poor gross motor coordination), HP:0100952 (Enlarged sylvian cistern), HP:0001251 (Ataxia), HP:0001250 (Seizure), HP:0002465 (Poor speech), HP:0007064 (Progressive language deterioration), HP:0011463 (Childhood onset), HP:0000572 (Visual loss), HP:0030511 (Bradyopsia), HP:0000550 (Undetectable electroretinogram), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0002120 (Cerebral cortical atrophy), HP:0001272 (Cerebellar atrophy)

CaseHPOFreeText: Onset was at age 5, with the first presenting phenotypes being motor problems. Marked cerebellar sulcal widening with subarachnoidal space expansion was seen by brain MRI at age 5. Ataxia and language degradation were observed at age 6. Cortical and cerebellar atrophy presented by brain MRI scan at age 7. Visual problems presented at age 7.5, specifically with inability to focus on moving objects. Seizures first presented at age 8.5, along with bilaterally extinguished ERG. Skin biopsy showed fingerprint-type intralysosomal inclusions.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide methods were not initially used, as clinical phenotypes were consistent with diagnosis of neuronal ceroid lipofuscinosis (NCL). Enzymatic tests ruled out defects in the CLN1, CLN2, and CLN10 loci, while CLN3, CLN6, and CLN8 defects were ruled out by Sanger sequencing of the coding regions. SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely locus to harbor the causative variant.

CaseMethod1: SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely candidate for further genotyping.

CaseMethod2: N/A

CaseGenotypingMethod: CLN5 mRNA was reverse transcribed, PCR-amplified, and subjected to Sanger sequencing. This process was performed for both affected and control individuals (parents and unaffected sibling).

Variant: Patient is homozygous for NM_006493.4(CLN5):c.924_925del (p.Leu309fs), (although this variant is referred to in the article as c.1072_1073delTT (p.Leu358AlafsX4)).

ClinVar: 56526

gnomAD: The variant is reported to have a maximum allele frequency of 0.0002603 (in the Latino / Admixed American population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77574801-AAT-A

VariantEvidence: The frameshift variant results in premature truncation and disrupts approximately 14% of the protein product at the C-terminus. Immunofluorescent detection of the exogenously expressed variant in COS7 cells shows aberrant localization to the ER in contrast to the wild-type localization to the lysosome (Figure 3).

CaseAddInfo: The patient's family has some degree of consanguinity, as parents are described as distantly related. Parents were heterozygous for the variant. Family relationships between individuals were verified.

CasePMIDs: N/A

PMID: 27228167

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.

PMID: 8659519

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.

FamilyLabel: Gong_1996_Three_Families

Family#PresentingHPOs: N/A

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

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

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

Ethnicity: Not specifically described

Race: Not specifically described

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

Family#Method1: Genome-wide linkage analysis

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

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

Affected: 7 genotyped

Unaffected: 5 genotyped

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

PublishedLOD: 5.99 (for the Dl1S987 marker)

eLOD: N/A

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

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

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

ClinVar: N/A

gnomAD: N/A

VariantEvidence: N/A

FamilyAddInfo: All three families are reportedly consanguineous.

FamilyPMIDs: N/A

Case#: Wang_2013_Proband_741, female, age 30 years at time of report, family origin not reported

CasePresentingHPOs: Retinal dystrophy HP:0000556, Attenuation of retinal blood vessels HP:0007843, Retinal pigment epithelial mottling HP:0007814, Patchy atrophy of the retinal pigment epithelium HP:0007791, Abnormality of macular pigmentation HP:0008002, Perifoveal ring of hyperautofluorescence HP:0030629, Abnormal retinal morphology on macular OCT HP:0030612, Mildly reduced visual acuity HP:0032037, Subretinal deposits HP:0031528

CaseHPOFreeText: The proband has a diagnosis of juvenile retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was subjected to capture-based next-generation sequencing panel that included 163 known retinal disease genes.

CaseMethod1: next-generation sequencing panel

CaseMethod2: SNP array and Sanger sequencing of PRPH2

CaseGenotypingMethod: The proband was genotyped by capture-based next-generation sequencing panel that included 163 known retinal disease genes. Sanger sequencing of PRPH2 was subsequently used to confirm the presence of the variant.

Variant: The proband harbors the NM_000322.5(PRPH2):c.554T>C (p.Leu185Pro) variant in the homozygous state.

ClinVar ID: 13165

gnomAD: The NM_000322.5(PRPH2):c.554T>C (p.Leu185Pro) variant is found in gnomAD v4.0.0 at a frequency of 0.00003587 in the European (non-Finnish) population, with 15 alleles / 418142 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/6-42721781-A-G?dataset=gnomad_r4

VariantEvidence: NM_000322.5(PRPH2):c.554T>C (p.Leu185Pro) is a missense variant with mouse knock-in evidence of a disease-causing effect in the heterozygous state (PMID: 11427722). Mouse phenotypes from PMID: 11427722 included reduced amplitude of dark-adapted bright flash electroretinogram a-wave HP:0030483 (Figure 4), Reduced OCT-measured macular thickness HP:0030607 (Figure 2), and immunoblot analysis showing reduced L185P in retinas, indicating instability or reduced transport to the outer segment (Figure 5b). Other experiments from PMID: 11297544 showed that the p.Leu185Pro variant successfully forms dimers but fails to assemble into higher order oligomers, particularly in the absence of wild-type PRPH2 (Figures 3, 5).

CaseAddInfo: The proband's parents are each heterozygous carriers of the variant who appear to be sub-clinically affected. The 56-year-old father showed macular pattern dystrophy with clear foveal changes, but normal visual acuity.

CasePMIDs: N/A

PMID: 23847139

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

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

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

Case#: Sergouniotis_2011_Proband_B-3, male, age 33 years, family ethnic origin described as European

CasePresentingHPOs: Reduced visual acuity HP:0007663, Constriction of peripheral visual field HP:0001133, Infantile onset HP:0003593, Strabismus HP:0000486, Nystagmus HP:0000639, Progressive night blindness HP:0007675, Moderate myopia HP:0031624, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654, Presenile cataracts HP:0007819, Nummular pigmentation of the fundus HP:0030505, Retinal pigment epithelial loss on macular OCT HP:0030611

CaseHPOFreeText: The proband received a diagnosis of Leber congenital amaurosis. His phenotype is described as similar to the other affected individuals, including "a distinct and unusual retinal appearance and a similar early onset of visual loss, suggesting both impaired retinal development and progressive retinal degeneration, involving both rod and cone pathways". The disease was described as mildly progressive. OCT showed distorted retinal microanatomy even in areas without cell death, possibly indicating disturbance of the early development of the neurosensory retina.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was previously genotyped by screening for previously-reported LCA-causing variants by microarray chip, with no molecular diagnosis.

CaseMethod1: screening for previously-reported LCA-causing variants by microarray chip

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

CaseGenotypingMethod: The proband was previously genotyped by screening for previously-reported LCA-causing variants by microarray chip, with no molecular diagnosis. Sanger sequencing of the KCNJ13 exons and intron-exon boundaries was subsequently performed.

Variant: The individual is homozygous for the NM_002242.4(KCNJ13):c.722T>C (p.Leu241Pro) variant.

ClinVar: 30332

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

VariantEvidence: NM_002242.4(KCNJ13):c.722T>C (p.Leu241Pro) is a missense variant that has no experimental evidence in this study but has separately been shown to severely decrease expression and abolish complex glycosylation of KCNJ13 (PMID: 30257863, Figure 10).

CaseAddInfo: The proband's family history is not known to include consanguinity but heterozygous parents originate from the same isolated geographic area.

CasePMIDs: N/A

ExperimentName: Genetically engineered Bbs7 homozygous knockout mouse

NonHumanModel: Mus musculus

GeneAlteration: The model animals harbor a homozygous replacement of Bbs7 exon 5 with a neomycin cassette, resulting in a frameshifted allele confirmed by western blotting to result in a null effect on the gene product.

ModelPhenotype: HP:0000546 (Retinal degeneration), HP:0032558 (Absent sperm flagella), HP:0001513 (Obesity), HP:0002119 (Ventriculomegaly), HP:0003251 (Male infertility), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0012258 (Abnormal axonemal organization of respiratory motile cilia), HP:0033524 (Abnormal sperm axoneme morphology)

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

ModelEvidence: This is a genetically engineered mouse model of biallelic Bbs7 disruption. The mutant animals with biallelic Bbs7 disrupion exhibit photoreceptor inner and outer segment loss (Figure 1), ventriculomegaly (Figure 1), reduced number of cilia and shortened cilia in brain tissue (Figure 2), abnormal axonemal structure / microtubule number abnormality in brain cilia (Figures 2F, 2G), lack of sperm flagella (Figure 3), Abnormal sperm axoneme microtubule organization (Figure 3), destabilization /absence of BBS2 in testes (Figure 4), and abnormal accumulation of some ciliary membrane proteins (dopamine D1 receptor, Figure 6) but not others (polycystin-1 or polycystin-2, Figure 5). Kidney cysts and polydactyly were looked for and found to be absent.

ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied a genetically engineered null variant disrupting Bbs7 expression.

Group Phenotypes

GroupName: Gliem_2015_Group_1

GroupPresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0000533 (Chorioretinal atrophy), HP:0000662 (Nyctalopia)

GroupHPOFreeText: Central and midperipheral atrophy, Central fibrosis, Dark adaptation problems, Progressive loss of visual acuity

GroupNotHPOs: N/A

GroupDemographics

NumberMales: 7

NumberFemales: 13

CountryOrigin: Germany

Ethnicity: Not mentioned

Race: Not mentioned

AgeRange: 52-79 at time of evaluation

TotalNumber: 20

GroupPreviousTesting: N/A

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

GroupAddInfo: The group consisted of 3 unrelated families.

PMID: 25766588

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

FamilyLabel: Gliem_2015_Family_1

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

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

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Germany

Family#PreviousTesting: N/A

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

Affected: 7

Unaffected: 1

Segregations: 7

PublishedLOD: N/A

eLOD: 2.1

AddSegregationInfo: N/A

ProbandLabel: Gliem_2000_Family_1_patient_II.1

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

CAID: CA411540328

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

PMID: 19379737

Gene: NR2E3

HGNC: 7974

Disease: enhanced S-cone syndrome

MONDO: 0100288

InheritancePattern: autosomal recessive

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

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

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

CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

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

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

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

ClinVar: 6272

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

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

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

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

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: targeted exome sequencing

CaseMethod2: Sanger sequencing of BBS1

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

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

ClinVar ID: 12143, 981241

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

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

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

CasePMIDs: N/A

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

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

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

ClinVarID: 5531

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

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

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

CasePMIDs: N/A

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

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

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

ClinVarID: 5530

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

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

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

CasePMIDs: N/A

PMID: 40172514

Gene: RP1L1

HGNC: 15946

Disease: occult macular dystrophy

MONDO: 0013316

InheritancePattern: autosomal dominant

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

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

PMID: 23023527

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

PMID: 32715858

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

FamilyLabel: DeBenedictis_2020_Family_1

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

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

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: Features of syndromic retinal dystrophy

CountryOrigin: N/A

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

Race: Caucasian

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

Family#Method1: Limited genetic testing for 13 candidate genes

Family#Method2: N/A

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

Affected: 2

Unaffected: 0

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

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: DiBenedetto_Patient_1

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

CAID: CA411539826

gnomAD: The variant is not found in gnomAD.

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

FamilyPMIDs: N/A

PMID: 35096838

Gene: KCNJ13

HGNC: 6259

Disease: Leber congenital amaurosis 16

MONDO: 0013613

InheritancePattern: autosomal recessive

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

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

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of PDE6A

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

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

ClinVar: 13111, 13112

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

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

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of PDE6A

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

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

ClinVar: 13110

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

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

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

CasePMIDs: N/A

FamilyLabel: Bowne_2011_Family_TCD-G

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

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

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

CountryOrigin: Ireland

Ethnicity: Not mentioned

Race: Not mentioned

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

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

Family#Method2: Candidate gene sequencing

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

Affected: 20

Unaffected: N/A

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

PublishedLOD: 3.6

eLOD: 6.32

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

ProbandLabel: Bowne_2011_Family_TCD-G_Patient_53

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

ClinVar: 750796

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

FamilyAddInfo: N/A

FamilyPMIDs: PMID: 20861475

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

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

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

CaseNotHPOs: HP:0000662 (Nyctalopia)

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing of CABP4

CaseMethod2: N/A

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

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

ClinVar ID: 1952

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

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

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

CasePMIDs: N/A

FamilyLabel: Jacobson_1995_Family_1

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

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

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: United States (mentioned in PMID:8981947)

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

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

Affected: 6

Unaffected: 2

Segregations: 5

PublishedLOD: N/A

eLOD: 1.5

AddSegregationInfo: N/A

ProbandLabel: Jacobson_1995_Family_1_Patient_III-5

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

CAID: CA411540415

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

PMID: 27124789

Gene: PDE6C

HGNC: 8787

Disease: cone dystrophy 4

MONDO: 0013129

InheritancePattern: recessive

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

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

PMID: 19610097

Gene: GPR143

HGNC: 20145

Disease: X-linked recessive ocular albinism

MONDO: 0021019

InheritancePattern: X-linked recessive

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

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

PMID: 31058429

GeneName: GNAT2

HGNC: 4394

Disease: achromatopsia 4

MonDO ID: MONDO_0013465

Inheritance: autosomal recessive

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: Sanger sequencing of PCR amplified exons from NYX

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

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

ClinVar: 99841

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

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