Cryptic exon activation caused by a novel deep-intronic splice-altering variant in Becker muscular dystrophy

An accurate genetic diagnosis of Becker muscular dystrophy (BMD) can be sometimes challenging due to deep intronic DMD variants. Here, we report on the genetic diagnosis of a BMD patient with a novel deep-intronic splice-altering variant in DMD.

The index case was a 3.8-year-old boy who was suspected of having a diagnosis of BMD based on his clinical, muscle imaging, and pathological features. Routine genomic detection approaches did not detect any disease-causing variants in him. Muscle-derived DMD mRNA studies, followed by genomic Sanger sequencing and in silico bioinformatic analyses, were performed in the patient.

DMD mRNA studies detected a cryptic exon-containing transcript and normally spliced DMD transcript in the patient. The cryptic exon-containing transcript encoded a frameshift and premature termination codon (NP_003997.1:p.[=,Asp2740Valfs*52]). Further genomic Sanger sequencing and bioinformatic analysis identified a novel deep-intronic splice-altering variant in DMD (c.8217 + 23338A > G). The novel variant strengthened a cryptic donor splice site and activated a cryptic acceptor splice site in the deep-intronic region of DMD intron 55, resulting in the activation of a new dystrophin cryptic exon found in the patient.

Our case report expands the genetic spectrum of BMD and highlights the essential role of deep-intronic cryptic exon-activating variants in genetically unsolved BMD patients.