316VP What you see is what it is: the tales of two brothers with rare intronic dystrophin gene duplication

• Published in: Neuromuscular disorders : NMD 2024-10, Vol.43, p.104441, Article 104441.511
• Main Authors: Khries, M., Gowda, V.
• Format: Article
• Language: English
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.520

We describe two brothers whose clinical presentation was consistent with Duchenne muscular dystrophy (DMD). The older brother was referred with a history of with motor delay and high creatine kinase (CK) level of up to 13,000. There was family history of probable muscular dystrophy in maternal uncle, and their mother was reported to be a DMD gene carrier in the context of limited information and verification due to the children being in care. Examination at 6 years showed evidence of mild proximal lower limb weakness, calves-hypertrophy, tendo-Achilles tightness and hypermobility in knees. The younger brother presented with only raised CK of 36,000 aged 3 years and over time, developed tendo-Achilles tightness and proximal lower limb weakness. Initial genetic studies including array comparative genomic hybridisation (aCGH) and dystrophin MLPA looking for deletions and duplications in all 79 DMD exons did not detect mutations. We further screened for variants in the dystrophin gene by next generation DNA sequencing and subsequently proceeded with dystrophin mRNA sequencing which again did not pick up any pathogenic variant. We arranged for muscle biopsy in the older brother which showed severe myopathic type changes consistent with a muscular dystrophy. The immunohistochemistry picture with dystrophins 1, 2 and 3 staining being almost completely negative on muscle fibre membranes was consistent with a diagnosis of Duchenne muscular dystrophy (DMD). We eventually decided to send a single nucleotide polymorphism (SNP) array for both brothers which revealed similar chromosomal imbalance at band p21.1 on the short arm of chromosome X due to copy number gain. This represents an intronic duplication in the dystrophin gene (arr[GRCh38] Xp21.1(31513438_31596491)x2 ). The clinical significance of this mutation was previously unknown. The boys are on steroid therapy and their trajectory is similar to that seen in other boys with DMD. We describe a new pathogenic variant of a rarer intronic duplication (compared to its exonic counterpart) in the DMD gene which in this case, is only detectable through an SNP array study. These cases also demonstrate that muscle biopsy is still useful in times of easy access to and numerous options for genetic investigations.