{"doi":"10.1093/hmg/ddab122","title":"<i>Cis</i>-acting modifiers in the <i>ABCA4</i> locus contribute to the penetrance of the major disease-causing variant in Stargardt disease","abstract":"Over 1200 variants in the ABCA4 gene cause a wide variety of retinal disease phenotypes, the best known of which is autosomal recessive Stargardt disease (STGD1). Disease-causing variation encompasses all mutation categories, from large copy number variants to very mild, hypomorphic missense variants. The most prevalent disease-causing ABCA4 variant, present in ~ 20% of cases of European descent, c.5882G > A p.(Gly1961Glu), has been a subject of controversy since its minor allele frequency (MAF) is as high as ~ 0.1 in certain populations, questioning its pathogenicity, especially in homozygous individuals. We sequenced the entire ~140Kb ABCA4 genomic locus in an extensive cohort of 644 bi-allelic, i.e. genetically confirmed, patients with ABCA4 disease and analyzed all variants in 140 compound heterozygous and 10 homozygous cases for the p.(Gly1961Glu) variant. A total of 23 patients in this cohort additionally harbored the deep intronic c.769-784C > T variant on the p.(Gly1961Glu) allele, which appears on a specific haplotype in ~ 15% of p.(Gly1961Glu) alleles. This haplotype was present in 5/7 of homozygous cases, where the p.(Gly1961Glu) was the only known pathogenic variant. Three cases had an exonic variant on the same allele with the p.(Gly1961Glu). Patients with the c.[769-784C > T;5882G > A] complex allele exhibit a more severe clinical phenotype, as seen in compound heterozygotes with some more frequent ABCA4 mutations, e.g. p.(Pro1380Leu). Our findings indicate that the c.769-784C > T variant is major cis-acting modifier of the p.(Gly1961Glu) allele. The absence of such additional allelic variation on most p.(Gly1961Glu) alleles largely explains the observed paucity of affected homozygotes in the population.","journal":"Human Molecular Genetics","year":2021,"id":155994,"datarank":0.6064576901751826,"base_score":4.04305126783455,"endowment":4.04305126783455,"self_citation_contribution":0.6064576901751826,"citation_network_contribution":0.0,"self_endowment_contribution":0.6064576901751826,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":56,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.95,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":659780,"name":"Jana Zernant","orcid":"0000-0003-3749-4799","position":1,"is_corresponding":false},{"id":444175,"name":"Takayuki Nagasaki","orcid":"0000-0002-7531-5176","position":2,"is_corresponding":false},{"id":296259,"name":"Laurie L. Molday","orcid":"0000-0003-4806-6327","position":3,"is_corresponding":false},{"id":660837,"name":"Pei-Yin Su","orcid":null,"position":4,"is_corresponding":false},{"id":493312,"name":"Gerald A. Fishman","orcid":null,"position":5,"is_corresponding":false},{"id":299097,"name":"Stephen H. Tsang","orcid":"0000-0001-9082-2427","position":6,"is_corresponding":false},{"id":296260,"name":"Robert S. Molday","orcid":"0000-0002-4479-1831","position":7,"is_corresponding":false},{"id":54649,"name":"Rando Allikmets","orcid":"0000-0002-3344-4447","position":8,"is_corresponding":false},{"id":233853,"name":"Winston Lee","orcid":"0000-0002-1777-8519","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:44:08.368845Z","pmid":"33909047","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}