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

Lookup NU author(s): Dr ursula Moore, Professor Volker StraubORCiD, Dr Rita Barresi, Professor Michela GuglieriORCiD, Dr Hannah Hayhurst, Dr Andrew Schaefer

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Abstract

© 2022 British Neuropathological Society. Aims: Dysferlinopathy is an autosomal recessive muscular dystrophy, caused by bi-allelic variants in the gene encoding dysferlin (DYSF). Onset typically occurs in the second to third decade and is characterised by slowly progressive skeletal muscle weakness and atrophy of the proximal and/or distal muscles of the four limbs. There are rare cases of symptomatic DYSF variant carriers. Here, we report a large family with a dominantly inherited hyperCKaemia and late-onset muscular dystrophy. Methods and Results: Genetic analysis identified a co-segregating novel DYSF variant [NM_003494.4:c.6207del p.(Tyr2070Metfs*4)]. No secondary variants in DYSF 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 four individuals, all between the fourth and sixth decades of life. All individuals heterozygous for the c.6207del variant had hyperCKaemia. Histological analysis of skeletal muscle biopsies across three generations showed clear dystrophic signs, including inflammatory infiltrates, 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 DYSF mRNA from patient muscle found that the variant, localised to the extreme C-terminus of dysferlin, does not activate post-transcriptional mRNA decay. Conclusions: We propose that this inheritance pattern may be underappreciated and that other late-onset muscular dystrophy cases with mono-allelic DYSF variants, particularly C-terminal premature truncation variants, may represent dominant forms of disease.

Publication metadata

Author(s): Folland C, Johnsen R, Botero Gomez A, Trajanoski D, Davis MR, Moore U, Straub V, Barresi R, Guglieri M, Hayhurst H, Schaefer AM, Laing NG, Lamont PJ, Ravenscroft G

Publication type: Article

Publication status: Published

Journal: Neuropathology and Applied Neurobiology

Year: 2022

Volume: 48

Issue: 7

Print publication date: 01/12/2022

Online publication date: 12/08/2022

Acceptance date: 07/08/2022

ISSN (print): 0305-1846

ISSN (electronic): 1365-2990

Publisher: John Wiley and Sons Inc.

URL: https://doi.org/10.1111/nan.12846

DOI: 10.1111/nan.12846

PubMed id: 35962550

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