Deletions and duplications of DMD exons are detected in 75–88% of probands with Duchenne or Becker muscular dystrophy (D/BMD). According to best practice guidelines, any such variant detected in an affected individual can be assumed to be causative.1 Does this mean that all DMD deletions and duplications can be assumed to be disease causing? In this article, we describe a tandem duplication of a DMD exon detected in multiple families with no history of muscular dystrophy (MD). We show that this duplication is a founder variant and suggest that it can be clinically classified as likely benign.

Although most frequently detected in MD probands, DMD deletions and duplications (herein described as CNVs) are also occasionally detected incidentally, for example, by microarray in children with non-muscular clinical phenotypes,2 3 or in asymptomatic individuals that are tested by whole exome sequencing.4 Such incidental findings can provoke significant anxiety for families, as they suggest that the proband and/or relatives may be at risk of D/BMD in the future. While deletions clearly disrupt the DMD gene, the same cannot always be said of duplications, as where in the genome they are inserted is often unknown. In this situation, an incidentally detected duplication is, by definition, a variant of uncertain significance that warrants further investigation.

A DMD CNV that we have encountered incidentally on multiple occasions is a duplication of exon 42 (herein denoted ‘DMD_E42_dup’). In five families, it was initially detected by microarray in male or female probands <10 years of age referred for various non-specific clinical reasons (eg, abnormal ultrasound, developmental delay, autistic features or spasticity). We have also detected DMD_E42_dup in an older adult female referred for multi-gene panel testing for dilated cardiomyopathy (DCM). She had no family history of DCM and was also heterozygous for a sarcomere gene …