Extremely hypomorphic and severe deep intronic variants in the locus result in varying Stargardt disease phenotypes.

Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the gene. Complete sequencing of the 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 have been identified in the latter group. We extended our analyses of deep intronic 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 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 ( < 1 × 10). The variant, which is not predicted to have any effect on splicing, is the first reported intronic "extremely hypomorphic allele" in the locus; that is, it is pathogenic only when in with a loss-of-function 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 locus can be accomplished by integrated clinical and genetic analyses.