Analysis of the ABCA4 genomic locus in Stargardt disease.

TitleAnalysis of the ABCA4 genomic locus in Stargardt disease.
Publication TypeJournal Article
Year of Publication2014
AuthorsZernant, J, Xie, YAngela, Ayuso, C, Riveiro-Álvarez, R, López-Martínez, M-Á, Simonelli, F, Testa, F, Gorin, MB, Strom, SP, Bertelsen, M, Rosenberg, T, Boone, PM, Yuan, B, Ayyagari, R, Nagy, PL, Tsang, SH, Gouras, P, Collison, FT, Lupski, JR, Fishman, GA, Allikmets, R
JournalHum Mol Genet
Date Published2014 Dec 20
KeywordsAlleles, ATP-Binding Cassette Transporters, Blacks, Case-Control Studies, Comparative Genomic Hybridization, Exons, Female, Gene Expression, Genes, Recessive, Genetic Loci, Genetic Variation, Heterozygote, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Introns, Macular Degeneration, Male, Mutation, Pedigree, Stargardt Disease, Whites

Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the ABCA4 gene. Complete sequencing of ABCA4 in STGD patients identifies compound heterozygous or homozygous disease-associated alleles in 65-70% of patients and only one mutation in 15-20% of patients. This study was designed to find the missing disease-causing ABCA4 variation by a combination of next-generation sequencing (NGS), array-Comparative Genome Hybridization (aCGH) screening, familial segregation and in silico analyses. The entire 140 kb ABCA4 genomic locus was sequenced in 114 STGD patients with one known ABCA4 exonic mutation revealing, on average, 200 intronic variants per sample. Filtering of these data resulted in 141 candidates for new mutations. Two variants were detected in four samples, two in three samples, and 20 variants in two samples, the remaining 117 new variants were detected only once. Multimodal analysis suggested 12 new likely pathogenic intronic ABCA4 variants, some of which were specific to (isolated) ethnic groups. No copy number variation (large deletions and insertions) was detected in any patient suggesting that it is a very rare event in the ABCA4 locus. Many variants were excluded since they were not conserved in non-human primates, were frequent in African populations and, therefore, represented ancestral, and not disease-associated, variants. The sequence variability in the ABCA4 locus is extensive and the non-coding sequences do not harbor frequent mutations in STGD patients of European-American descent. Defining disease-associated alleles in the ABCA4 locus requires exceptionally well characterized large cohorts and extensive analyses by a combination of various approaches.

Alternate JournalHum Mol Genet
PubMed ID25082829
PubMed Central IDPMC4245042
Grant ListR01 EY021237 / EY / NEI NIH HHS / United States
R01 EY018213 / EY / NEI NIH HHS / United States
R24 EY019861 / EY / NEI NIH HHS / United States
EY019007 / EY / NEI NIH HHS / United States
EY019861 / EY / NEI NIH HHS / United States
T32 EY013933 / EY / NEI NIH HHS / United States
EY021237 / EY / NEI NIH HHS / United States
EY021163 / EY / NEI NIH HHS / United States
R01 EY021163 / EY / NEI NIH HHS / United States

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