A novel point mutation affecting Asn76 of dystrophin protein leads to dystrophinopathy

Area of Science:

• Genetics
• Molecular Biology
• Neuromuscular Disorders

Background:

• Duchenne and Becker muscular dystrophies (DMD/BMD) result from mutations in the DMD gene.
• Missense mutations are an infrequent cause of DMD/BMD, necessitating precise diagnostic approaches.
• Early diagnosis is critical for managing these progressive neuromuscular conditions.

Observation:

• A six-month-old male presented with hypotonia and delayed motor development, with highly elevated creatine kinase levels.
• Initial multiplex ligation-dependent probe amplification (MLPA) suggested an exon 4 deletion, but this was not confirmed.
• Genetic sequencing identified a novel de novo missense mutation (c.227A>T, p.Asn76Ile) in the dystrophin N-terminal actin-binding domain.

Findings:

• The identified mutation (p.Asn76Ile) was predicted to be highly destabilizing to the dystrophin N-terminal actin-binding domain.
• The false positive MLPA result was attributed to the mutation's location at the probe ligation site.
• Dystrophin immunohistochemistry on muscle biopsy was suggestive of Becker muscular dystrophy, indicating protein malfunction.

Implications:

• Highlights the critical need for confirmatory testing of single-exon deletions identified by MLPA.
• Describes a novel, destabilizing missense mutation in the DMD gene, expanding the spectrum of known pathogenic variants.
• Emphasizes the importance of comprehensive genetic analysis for diagnosing rare forms of dystrophinopathies.