Submission Details

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).