D.O.2 Microarray testing for developmental delay reveals an expanded clinical spectrum of dystrophinopathies

Abstract The dystrophinopathies are allelic muscular dystrophies caused by X-linked recessive mutations in dystrophin, with only rare reports of asymptomatic adult males. The static cognitive impairment seen in dystrophinopathies is thought to be due to altered expression of dystrophin isoforms, but has only once been described in the absence of muscle weakness. We identified a cohort of patients with unexpected copy number variants (CNV) in the dystrophin gene, on microarrays performed for developmental delay or intellectual disability, in whom muscle weakness was minimal or absent. Subjects with a dystrophin CNV referred to the neurology or genetics departments at RCH Melbourne or GHSV were assessed. An additional family was identified from the CHW, and included. Twelve probands had a CNV in the dystrophin gene on microarray testing. Eight (seven male, one female; seven deletions, one duplication), age 0–9 years, had atypical phenotypes as described above. CNVs were found in 10 family members (five males and five females), including three asymptomatic adult males. In all but one family, MLPA confirmed loss of exons. Muscle weakness was absent or minimal. Serum CK was normal or mildly elevated. Muscle biopsy revealed morphologically normal muscle with normal dystrophin immunoreactivity. Microarray testing has revealed an extended spectrum of clinical phenotypes associated with mutations in dystrophin, that may include isolated developmental delay and asymptomatic individuals. Further study is required to understand the molecular basis of the apparent absence of muscle pathology in these patients, and the relationship of the dystrophin deletion to cognitive impairment.