Case Description: 58-year-old male with history of chronic mild transaminase elevation presented for progressive muscle weakness and atrophy of proximal muscles in his arms and legs beginning suddenly in his late 40s. On examination, was atrophy of the bilateral deltoids, right scapular winging, and mild weakness of deltoids, biceps, iliopsoas and hip extensors without bulbar or cervical weakness. Labs showed marked elevated CK and mildly elevated transaminases. MRI of the bilateral thighs revealed asymmetric fatty atrophy and edema.
Testing for spinal muscular atrophy, myositis, myopathies, Duchenne muscular dystrophy and myotonic dystrophies were negative. A variant of uncertain significance was identified in the DYSF gene c.866C>T. Biopsy of the left vastus lateralis demonstrated type 2 fiber predominance, fiber-type grouping and absence of sarcolemmal dysferlin. RNA sequencing of the DYSF gene demonstrated a variant of uncertain significance at c.866C>T and at c.2926-14G>A which has been previously reported in association with late onset limb-girdle muscular dystrophy.
RNA sequencing of DYSF demonstrated altered splicing (at the exon 27-exon 28 junction) likely due to an intronic variant (c.2926-14G>A) which appears to create a new splice acceptor site. The altered splicing was not seen in transcripts that contained the previously known variant, c.866C>T. This suggests that the intronic variant is in trans to the known pathological variant, and results in reduced levels of normal transcripts. We conclude that given the absent dysferlin staining seen on muscle biopsy, the compound heterozygous DYSF variants, c.866C>T and c.2926-14G>A, are indeed pathogenic and cause a dysferlin deficiency with a later onset LGMD 2B phenotype. This case demonstrates the utility of RNA sequencing to identify alternate splice products and led to identification of a novel pathogenic variant the DYSF gene. This case also demonstrates the concept of leaky splice sites leading to production of some normal gene