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. 2014 Dec 20;23(25):6797-806.
doi: 10.1093/hmg/ddu396. Epub 2014 Jul 31.

Analysis of the ABCA4 genomic locus in Stargardt disease

Jana Zernant  1 , Yajing Angela Xie  1 , Carmen Ayuso  2 , Rosa Riveiro-Alvarez  2 , Miguel-Angel Lopez-Martinez  2 , Francesca Simonelli  3 , Francesco Testa  3 , Michael B Gorin  4 , Samuel P Strom  5 , Mette Bertelsen  6 , Thomas Rosenberg  6 , Philip M Boone  7 , Bo Yuan  7 , Radha Ayyagari  8 , Peter L Nagy  9 , Stephen H Tsang  10 , Peter Gouras  1 , Frederick T Collison  11 , James R Lupski  7 , Gerald A Fishman  11 , Rando Allikmets  12
Affiliations

Analysis of the ABCA4 genomic locus in Stargardt disease

Jana Zernant et al. Hum Mol Genet. .

Abstract

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.

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Figures

Figure 1.
Figure 1.
Pedigrees segregating the new ABCA4 intronic variants with STGD1.
Figure 2.
Figure 2.
Analysis of the c.5196+1137G>A variant in M. mulatta. (A) Alignment of the Homo sapiens chromosome1: 94 484 046–94 483 967, GRCh37.p13 Primary Assembly, with M. mulatta respective sequences. ABCA4 intronic position c.5196 + 1137G is marked with large font in bold. Differences in macaque sequence compared with human are designated with letters. (B) Confirmation of correct splicing of ABCA4 exons 36 and 37 in a c.5196+1137A macaque retina in RT-PCR analysis. No alternate splicing products were detected.
See this image and copyright information in PMC

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