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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.

Analysis of the ABCA4 genomic locus in Stargardt disease