Extremely hypomorphic and severe deep intronic variants in the <i>ABCA4</i> locus result in varying Stargardt disease phenotypes

Abstract

Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the <i>ABCA4</i> gene. Complete sequencing of the <i>ABCA4</i> locus in STGD1 patients identifies two expected disease-causing alleles in ∼75% of patients and only one mutation in ∼15% of patients. Recently, many possibly pathogenic variants in deep intronic sequences of <i>ABCA4</i> have been identified in the latter group. We extended our analyses of deep intronic <i>ABCA4</i> variants and determined that one of these, c.4253+43G>A (rs61754045), is present in 29/1155 (2.6%) of STGD1 patients. The variant is found at statistically significantly higher frequency in patients with only one pathogenic <i>ABCA4</i> allele, 23/160 (14.38%), MAF = 0.072, compared to MAF = 0.013 in all STGD1 cases and MAF = 0.006 in the matching general population (<i>P</i> < 1 × 10^-7). The variant, which is not predicted to have any effect on splicing, is the first reported intronic "extremely hypomorphic allele" in the <i>ABCA4</i> locus; that is, it is pathogenic only when in <i>trans</i> with a loss-of-function <i>ABCA4</i> allele. It results in a distinct clinical phenotype characterized by late onset of symptoms and foveal sparing. In ∼70% of cases the variant was allelic with the c.6006-609T>A (rs575968112) variant, which was deemed nonpathogenic. Another rare deep intronic variant, c.5196+1056A>G (rs886044749), found in 5/834 (0.6%) of STGD1 cases is, conversely, a severe allele. This study determines pathogenicity for three noncoding variants in STGD1 patients of European descent accounting for ∼3% of the disease. Defining disease-associated alleles in the noncoding sequences of the <i>ABCA4</i> locus can be accomplished by integrated clinical and genetic analyses.