PMID: 8474143

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

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

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

Case#: Jauregui_2018_Patient_1, male, 53 years of age at onset, Scottish ancestry

CasePresentingHPOs: HP:0003581 (Adult onset), HP:0000662 (Nyctalopia), HP:0007994 (Peripheral visual field loss), HP:0000533 (Chorioretinal atrophy), HP:0030979 (Dilatation of large choroidal vessels), HP:0007703 (Abnormality of retinal pigmentation), HP:0007663 (Reduced visual acuity), HP:0200070 (Peripheral retinal atrophy), HP:0007722 (Retinal pigment epithelial atrophy), HP:0000518 (Cataract)

CaseHPOFreeText: The patient presented at age 53 with nyctalopia and peripheral visual loss.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: 31-gene sequencing panel

CaseMethod2: N/A

CaseGenotypingMethod: Variants in CHM and 29 other genes involved in Retinitis pigmentosa or Leber congenital amaurosis were excluded by genotyping panel, which also detected the variant in RPE65.

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

ClinVar: 750796

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

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

CaseAddInfo: The possibility of family consanguinity was not mentioned.

CasePMIDs: N/A

PMID: 9808841

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

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

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

Case#: Hull_2016_Patient_2.1, female, 45 years of age at onset, Irish ancestry

CasePresentingHPOs: HP:0003581 (Adult onset), HP:0007663 (Reduced visual acuity), HP:0001141 (Severely reduced visual acuity), HP:0200065 (Chorioretinal degeneration), HP:0000580 (Pigmentary retinopathy), HP:0030474 (Undetectable dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram)

CaseHPOFreeText: The patient presented at age 45 with central visual disturbance. Anterior retina was well-preserved.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: Variants in REP1 and PRPH2 were initially excluded.

CaseMethod1: Candidate gene sequencing

CaseMethod2: Bidirectional, targeted Sanger sequencing within the RPE65 locus

CaseGenotypingMethod: Bidirectional Sanger sequencing of exon 13 of the RPE65 gene and flanking sequences

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

ClinVar: 750796

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

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

CaseAddInfo: The possibility of family consanguinity was not mentioned.

CasePMIDs: N/A

Case#: Hull_2016_Patient_1.2, male, 18 years of age at onset, Irish ancestry

CasePresentingHPOs: HP:0003581 (Adult onset), HP:0007663 (Reduced visual acuity), HP:0000533 (Chorioretinal atrophy), HP:0000662 (Nyctalopia), HP:0007722 (Retinal pigment epithelial atrophy), HP:0000533 (Chorioretinal atrophy), HP:0030602 (Abnormal fundus autofluorescence imaging), HP:0000510 (Rod-cone dystrophy), HP:0008179 (Decreased Arden ratio of electrooculogram), HP:0000512 (Abnormal electroretinogram)

CaseHPOFreeText: The patient presented at age 18 with nyctalopia, progressed to central visual disturbance at age 33, and was limited to hand movement vision by age 48, with preserved peripheral vision.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: Variants in REP1 and PRPH2 were initially excluded.

CaseMethod1: Candidate gene sequencing

CaseMethod2: Bidirectional, targeted Sanger sequencing within the RPE65 locus

CaseGenotypingMethod: Bidirectional Sanger sequencing of exon 13 of the RPE65 gene and flanking sequences

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

ClinVar: 750796

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

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

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Morimura_1998_Family_9190_Patient_II-1, female, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

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

Variant: The proband is a compound heterozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.370C>T (p.Arg124Ter) and NM_000329.3(RPE65):c.962dup (p.Asn321fs) variants.

ClinVar: 98866, 98902

gnomAD: The NM_000329.3(RPE65):c.370C>T (p.Arg124Ter) variant has a maximum allele frequency of 0.0003676 (within the African / African-American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68910339-G-A The NM_000329.3(RPE65):c.962dup (p.Asn321fs) variant has a maximum allele frequency of 0.0001148 (within the African / African-American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68904660-A-AT

VariantEvidence: NM_000329.3(RPE65):c.370C>T (p.Arg124Ter) is a paternal nonsense variant predicted to either trigger NMD or truncate 77% of the protein product. NM_000329.3(RPE65):c.962dup (p.Asn321fs) is a maternal frameshift variant predicted to either trigger NMD or truncate 40% of the protein product.

CaseAddInfo: Genotyping of the proband's parents revealed that the variants are in trans. The possibility of parental consanguinity was not mentioned.

CasePMIDs: N/A

Case#: Morimura_1998_Family_E070_Patient_III-4, female, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of isolate retinitis pigmentosa (later recategorized to recessive retinitis pigmentosa) indicates that the proband maintained central vision during the first decade of life and subsequently experienced severe vision loss.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

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

Variant: The proband is a compound heterozygote harboring the NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) and NM_000329.3(RPE65):c.1355T>G (p.Val452Gly) variants.

ClinVar: 13115, 13116

gnomAD: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant has a maximum allele frequency of 0.0002406 (in the African / African-American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68910541-G-A The NM_000329.3(RPE65):c.1355T>G (p.Val452Gly) variant has a maximum allele frequency of 0.00005660 (in the Latino / Admixed American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68896843-A-C

VariantEvidence: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) missense variant was also found in apparently unrelated patients diagnosed with Leber congenital amaurosis (Figure 2B). A separate publication (PMID: 16754667) expressed this missense variant in non-patient cells and showed that it abolished the isomerohydrolase activity of the protein product, reduced its stability, and shifted the subcellular localization from predominantly membrane-associated to predominantly cytosolic. The NM_000329.3(RPE65):c.1355T>G (p.Val452Gly) variant is a missense mutation without evidence of gene impact.

CaseAddInfo: The two variants are strongly suspected to be in trans, but one parent was not genotyped. A heterozygous carrier of the NM_000329.3(RPE65):c.1355T>G (p.Val452Gly) variant was found to be unaffected. Potential consanguinity between the parents was not reported.

CasePMIDs: N/A

Case#: Morimura_1998_Family_9145_Patient_II-1, female, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

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

Variant: The proband is a homozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.1418T>A (p.Val473Asp) variant.

ClinVar: 98846 (homozygous)

gnomAD: The NM_000329.3(RPE65):c.1418T>A (p.Val473Asp) variant is not found within gnomAD.

VariantEvidence: NM_000329.3(RPE65):c.1418T>A (p.Val473Asp) is a missense variant with unknown impact on gene function.

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

CasePMIDs: N/A

Case#: Morimura_1998_Family_7828_Patient_III-4, male, age not specified, from family originating in the Dominican Republic

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

CaseHPOFreeText: While specific phenotypes are not provided, the diagnosis of retinitis pigmentosa indicates that the affected family members maintained central vision during the first decade of life and subsequently experienced severe vision loss.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

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

Variant: The proband is a compound heterozygote harboring the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) and NM_000329.3(RPE65):c.1207_1210dup (p.Glu404fs) variants.

ClinVar: 13118, 98831

gnomAD: Neither the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) variant nor the NM_000329.3(RPE65):c.1207_1210dup (p.Glu404fs) variant is found within gnomAD.

VariantEvidence: The paternal frameshift variant is predicted to either trigger NMD or disrupt 24% of the protein product. The maternal missense variant does not have evidence of gene impact.

CaseAddInfo: The two variants were confirmed to be in trans, and heterozygous carriers were found to be unaffected. Potential consanguinity between the parents was not reported, at least within the first generation of the pedigree.

CasePMIDs: N/A

Case#: Gu_1997_Family_PMK18_Patient_V-1, male, unknown age, Indian ethnicity

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0001098 (Abnormal fundus morphology)

CaseHPOFreeText: Onset is early and course of disease is severe. The appearance of the fundus in adulthood is considered characteristic of retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing consisted of linkage analysis using microsatellite repeat markers (D152803, DJS1665, D1S438 and DJS1728) associated with the RPE65 locus.

CaseMethod1: Linkage analysis

CaseMethod2: PCR products were screened by restriction digest analysis using the Msel endonuclease.

CaseGenotypingMethod: The patient sample was subjected to PCR and Sanger sequencing of all RPE65 exons.

Variant: 4 out of 5 affected individuals are homozygous for the NM_000329.3(RPE65):c.858+1G>T variant.

ClinVar: 98893

gnomAD: The NM_000329.3(RPE65):c.858+1G>T variant is not shown in gnomAD.

VariantEvidence:

CaseAddInfo: The family pedigree shows consanguinity in the parents of all affected individuals. One of the affected individuals is a heterozygous carrier of the variant, rather than a homozygote.

CasePMIDs: N/A

PMID: 17848510

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

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

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

PMID: 9326927

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

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

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