Identification of a novel heterozygous DYSF variant in a large family with a dominantly‐inherited dysferlinopathy. (20th August 2022)

• Record Type: Journal Article
• Authors: Folland, Chiara; Johnsen, Russell; Botero Gomez, Adriana; Trajanoski, Daniel; Davis, Mark R.; Moore, Ursula; Straub, Volker; Barresi, Rita; Guglieri, Michela; Hayhurst, Hannah; Schaefer, Andrew M.; Laing, Nigel G.; Lamont, Philipa J.; Ravenscroft, Gianina
• Is Part Of: Neuropathology & applied neurobiology. Volume 48:Number 7(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-08-20
• Subjects: dominant -- dysferlin -- dysferlinopathy -- hyperCKaemia -- myopathy -- NGS; Nervous system -- Diseases -- Pathology -- Periodicals; Nervous system -- Diseases -- Periodicals; 616.8
• DOI: 10.1111/nan.12846
• Languages: English
• ISSNs: 0305-1846

Abstract

Abstract: 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. Abstract : Dysferlinopathy is a rare, autosomal recessive muscular dystrophy, caused by bi‐allelic loss‐of‐function variants in DYSF . Here we describe a large family with a dominantly inherited hyperCKaemia and late‐onset progressive muscular dystrophy co‐segregating with a novel heterozygous DYSF frameshift variant. We propose that dominant dysferlinopathy may be underappreciated and should be considered for patients with a mono‐allelic variant if a secondary DYSF variant cannot be resolved after thorough genetic testing and analysis, particularly for those with C‐terminal premature protein truncation variants.