O.11 Identification of a novel heterozygous DYSF variant in a large family with a dominantly-inherited dysferlinopathy

Abstract

Dysferlinopathy is an autosomal recessive muscular dystrophy, caused by bi-allelic variants in the gene encoding dysferlin (<i>DYSF</i>). Onset typically occurs in the second to third decade and is characterised by slowly progressive skeletal muscle weakness and atrophy of proximal and/or distal muscles of the limb girdles. There are rare cases of symptomatic <i>DYSF</i> variant carriers. Here, we report a large family with a dominantly inherited hyperCKemia and late-onset muscular dystrophy. Genetic analysis identified a co-segregating novel <i>DYSF</i> variant [NM_003494.4: c.6207del, p.(Tyr2070Metfs*4)]. No secondary variants in <i>DYSF</i> or other dystrophy-related genes were identified on whole genome sequencing and analysis of the proband's DNA. Skeletal muscle involvement was milder and later onset than typical dysferlinopathy presentations; these clinical signs manifested in only three individuals, all between the fourth and sixth decades of life. All individuals heterozygous for the c.6207del variant had hyperCKemia. Histological analysis of skeletal muscle biopsies across three generations showed clear dystrophic signs, including inflammatory infiltrate, regenerating myofibres, increased variability in myofibre size, and internal nuclei. Muscle magnetic resonance imaging revealed fatty replacement of muscle in two individuals. Western blot and immunohistochemical analysis of muscle biopsy demonstrated consistent reduction of dysferlin staining. Allele-specific quantitative PCR analysis of <i>DYSF</i> mRNA from patient muscle found that the variant, localised to the extreme C-terminus of dysferlin, does not activate post-transcriptional mRNA decay. We propose that this inheritance pattern may be underappreciated and that other late-onset muscular dystrophy cases with mono-allelic <i>DYSF</i> variants, particularly C-terminal premature truncation variants, may represent dominant forms of disease.