ABCA4

Inheritance Pattern: AR

Disease ID:MONDO:0011137

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0011395

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009549

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0007932

Submitter: ClinGen

The *ABCA4* gene was first reported in relation to autosomal recessive Stargardt disease in 1997 (PMID: 9054934), with subsequent phenotypic testing of carriers in Stargardt disease families leading to the hypothesis that monoallelic *ABCA4* loss-of-function may increase susceptibility to age-related macular degeneration (Allikmets et al., 1997, PMID: 9295268). Reported clinical features among affected heterozygous carriers included visual impairment with onset at age 55 years or later, macular degeneration, including pigmentary changes in the macula and subtle but progressive attenuation of the central ellipsoid zone, and/or choroidal neovascularization (PMID: 9295268, PMID: 10396622, PMID: 10486215, PMID: 36338671). Subsequent reports have expanded the phenotypic range of recessive *ABCA4*-related disease to include additional diagnoses of retinitis pigmentosa (PMID: 9070931), cone-rod dystrophy (PMID: 18285826, 12796258), early-onset severe retinal dystrophy (PMID: 16546111), and fundus flavimaculatus (PMID: 9781034). Disease severity among the recessive cases depends in part on the combination of variants and variant types present (PMID: 9466990, PMID: 33261146, PMID: 34874912). Studies of age-related macular degeneration in larger cohorts have presented conflicting evidence regarding the statistical significance of *ABCA4* variants as a potential association (PMID: 10880298, PMID: 11346402, PMID: 11328725, PMID: 21106043, PMID: 10958763, PMID: 26720470). At least some attempts to identify ABCA4-related cases within age-related macular degeneration cohorts have failed to identify causal heterozygous *ABCA4* variants, but did identify cases with phenotypes more accurately described as late-onset macular dystrophy harboring biallelic *ABCA4* variants, some of which were compound heterozygotes harboring the hypomorphic NM_000350.3(ABCA4):c.5603A>T (p.Asn1868Ile) variant in trans with a known disease-causing variant (PMID: 32717343). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the reported autosomal dominant cases were found to differ from the more established autosomal recessive cases in their mode of inheritance but to overlap in their underlying molecular mechanism (*ABCA4* loss-of-function) and similar but milder phenotypes. On the other hand, remaining doubts about the validity of the relationship between *ABCA4* and age-related macular degeneration led to the recommendation to curate the recessive cases under a lumped disease entity referred to as ABCA4-related retinopathy while splitting the association with autosomal dominant cases into the present gene curation, under the term age-related macular degeneration 2. Seven suspected disease-causing variants have been scored as part of this curation (one nonsense, two frameshift, one affecting splicing, and four missense), which have been collectively reported in seven probands in three publications (PMID: 9295268, PMID: 10396622, PMID: 10486215). All of the probands scored in this curation reportedly harbored monoallelic *ABCA4* variants, with the mechanism of pathogenicity proposed to be monoallelic loss of ABCA4 function conferred by null and/or hypomorphic variants. The scored cases are representative of a much larger body of published patients that were not included in ths curation. However, this genetic evidence was not scored due to remaining doubts and conflicting evidence about the causality of the variant identified and the absence of an identified second *ABCA4* variant on the other allele. Segregation evidence did not contribute to the scoring of this curation. This gene-disease association is supported by experimental evidence that *ABCA4* encodes an N-retinylidene-phosphatidylethanolamine flippase that facilitates the removal of all-trans-retinal from photoreceptor disc membranes as a key step in restoring light sensitivity after photoexcitation (PMID: 22735453, PMID: 24707049). *ABCA4* is highly specifically expressed in the human retina and retinal pigment epithelium (PMID: 30239781). Mice with heterozygous *Abca4* knockout exhibit lipofuscin accumulation, slower recovery of rod electroretinogram sensitivity following light exposure, and thickening and disorganization of the retinal pigment epithelium in aged mice (PMID: 11431429). The scoring of this experimental evidence has been moderately decreased based on lack of clarity about the underlying disease mechanism in human patients. In summary, *ABCA4* has a Disputed associated with autosomal dominant age-related macular degeneration 2. This classification has been reached despite compelling experimental evidence linking *ABCA4* to inherited retinal disease, and reflects doubts regarding the genetic evidence for the dominant mode of inheritance. This includes conflicting findings of association from large case-control and genome-wide association studies, with at least some evidence of cases initially diagnosed as age-related macular degeneration but subsequently reclassified as late-onset macular dystrophy with a compound heterozygous *ABCA4* genotype that is consistent with milder presentation. This classification was approved by the ClinGen Retina GCEP on the meeting date March 6th, 2025 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0800406

Submitter: ClinGen

The *ABCA4* gene (initially referred to as the *ABCR* gene) was first cloned and reported in relation to autosomal recessive Stargardt disease and fundus flavimaculatus in 1997 (Allikmets et al.; PMID: 9054934). The clinical phenotype of Stargardt disease was first described in 1909 by Karl Bruno Stargardt [Stargardt, K. "Über familiäre, progressive Degeneration in der Maculagegend des Auges." Albrecht von Graefes Archiv für Ophthalmologie 71.3 (1909): 534-550]. Stargardt disease phenotype can vary greatly, though the condition often presents with bilateral, progressive central or pericentral vision loss starting in adolescence or young adulthood, macular atrophy, and characteristic yellow/white retinal flecks around the macula seen on fundus exam (PMIDs: 9054934, 9781034, 28044389, 34874912). Stargardt disease, one of the most common inherited retinal disorders, has an estimated prevalence of 1/8,000-1/10,000 (PMID: 30578500), and *ABCA4* carrier frequency in the general population has been estimated to be as high as 1/10 to 1/40, although not all combinations of variants are expected to cause disease (PMIDs: 11379881, 14517951, 31964843). In addition to Stargardt disease 1 (MIM: 248200), *ABCA4* has been associated with the following autosomal recessive disease entities: cone-rod dystrophy 3 (MIM: 604116), fundus flavimaculatus (MIM: 248200), retinal dystrophy, early-onset severe (MIM: 248200), and retinitis pigmentosa 19 (MIM: 601718). For this curation, the autosomal recessive disease entities have been lumped into one disease entity, *ABCA4*-related retinopathy. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. It has been suggested that these autosomal recessive *ABCA4*-related retinopathies comprise a phenotypic spectrum, with disease severity depending in part on the combination of variants and variant types present (PMIDs: 9466990, 33261146, 34874912). Many individual disease-causing *ABCA4* variants have been associated with multiple phenotypes (PMID: 34874912). Of note, while we included cases from the literature with all of the aforementioned autosomal recessive *ABCA4*-related diagnoses, the Retina GCEP members feel that there is not strong evidence that *ABCA4* causes classic retinitis pigmentosa. It has been suggested that cases of retinitis pigmentosa-like disease related to biallelic *ABCA4* variants are more likely to be representative of advanced/severe cone-rod dystrophy with panretinal degeneration, rather than typical retinitis pigmentosa (PMID: 23755871). To account for a spectrum of retinal phenotypes that may be caused by variants in this gene, and in accordance with the ClinGen Lumping and Splitting guidelines, the disease entity used for this curation is *ABCA4*-related retinopathy (MONDO:0800406). The *ABCA4* gene has also been implicated in autosomal dominant age-related macular degeneration (MIM: 153800; PMIDs: 10458172, 10880298). However, there is conflicting evidence regarding the association of *ABCA4* and age-related macular degeneration (PMIDs: 10958763, 11346402, 26720470). This potential autosomal dominant association will be assessed separately in a future curation. 27 variants (including missense, nonsense, frameshift, splice site, large deletion, deep intronic, and complex alleles) that have been reported in 23 probands in 8 publications (PMIDs: 9054934, 9466990, 9781034, 10958761, 15494742, 18285826, 26527198, 28559085) are included in this curation. Probands included in this curation were reported to have the following clinical diagnoses: Stargardt disease, fundus flavimaculatus, cone-rod dystrophy, cone dystrophy, pattern dystrophy, and retinitis pigmentosa. More genetic evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Of note, the Retina GCEP opted to exclude the common hypomorphic and/or low penetrant variants, *ABCA4* c.5603A>T (p.Asn1868Ile), *ABCA4* c.2588G>C (p.Gly863Ala), and *ABCA4* c.5882G>A (p.Gly1961Glu) from being included as countable variants in this curation given the abundance of other genetic evidence and remaining uncertainty regarding penetrance of those variants. However, we recognize that p.Asn1868Ile, p.Gly863Ala, and p.Gly1961Glu have been reported to be disease causing in certain contexts, especially when in trans with another severe/LOF *ABCA4* variant (PMIDs: 10090887, 28327576, 28446513, 29971439). The mechanism of pathogenicity for autosomal recessive *ABCA4*-related retinopathy is reported to be LOF. This gene-disease association is also supported by experimental evidence (e.g. animal models, expression studies, *in vitro* functional assays, etc.) (PMIDs: 9054934, 9092582,10412977, 10888868, 20238056, 22735453, 22886305, 24707049). ABCA4 is transporter of retinoid compounds, and it prevents accumulation of 11-cis-retinal and facilitates clearance of all-trans-retinal following photoexcitation (PMIDs: 22735453, 24707049). *ABCA4* gene expression is localized to photoreceptors. While the ABCA4 protein was initially found to be localized to the outer segment of rods, it was later demonstrated to localize to foveal and peripheral cone cells as well (PMIDs: 9054934, 9092582, 10888868). *Abcr-/-* mice have features consistent with human disease, including accumulation of lipofuscin pigment in RPE, photoreceptor degeneration, and delayed dark adaptation (PMID: 10412977, 20238056, 22886305), and nanoparticle-mediated *ABCA4* delivery showed improved recovery of dark adaptation and reduced lipofuscin accumulation in knockout mice (PMID: 22886305). More experimental evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) has been reached. In summary, *ABCA4* is definitively associated with autosomal recessive *ABCA4*-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Retina GCEP on the meeting date October 6, 2022 (SOP Version 9).

Inheritance Pattern: AD

Disease ID:MONDO:0015993

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0800406

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0019353

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0011395

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009549

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0011395

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0009549

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AD

Disease ID:MONDO:0007932

Submitter: PanelApp Australia