Autosomal-recessive Stargardt disease (STGD1) is hallmarked by a large proportion of patients with a single heterozygous causative variant in the disease geneABCA4.Braun et al. (2013)reported deep intronic variants ofABCA4in STGD1 patients with one coding variant, prompting us to perform an augmented screen in 131 Belgian STGD1 patients with one or noABCA4variant to uncover deep intronic causalABCA4variants. This revealed a second variant in 28.6% of cases. Twenty-six percent of these carry the same causal variant c.4539+2001G>A (V4). Haplotyping in V4 carriers showed a common region of 63 kb, suggestive of a founder mutation. Genotype–phenotype correlations suggest a moderate-to-severe impact of V4 on the STGD1 phenotype. In conclusion, V4 occurs in a high fraction of Belgian STGD1 patients and represents the first deep intronic founder mutation inABCA4. This emphasizes the importance of augmented molecular genetic testing ofABCA4in Belgian STGD1.
A and B: The deep intronic ABCA4 variant V4 (c.4539+2001G>A), which has a predicted effect on splicing, occurs in almost 26% of a Belgian STGD1 cohort with one identified coding mutation. It is part of a shared haplotype block in these patients, indicative for a founder mutation. C. V4 has a moderate-to-severe effect on the STGD1 phenotype.