An in‐frame pseudoexon activation caused by a novel deep‐intronic variant in the dysferlin gene

The precise detection and interpretation of pathogenic DYSF variants are sometimes challenging, largely due to rare deep-intronic splice-altering variants. Here, we report on the genetic diagnosis of a male patient with dysferlinopathy. He remained genetically unsolved after routine exonic detection approaches that only detected a novel heterozygous frameshift variant (c.407dup, p.Thr137Tyrfs*11) in DYSF exon 5. Via muscle-derived DYSF mRNA studies, we identified a novel deep-intronic DYSF variant in the other allele (c.1397 + 649C > T), which causing in-frame alterations in DYSF mRNA and protein structure and confirmed his genetic diagnosis of dysferlinopathy. Our study emphasizes the potential role of undetected deep-intronic splice-altering variants in monogenic diseases.