Submission Details

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).