Journal article
Identification of a novel heterozygous DYSF variant in a large family with a dominantly‐inherited dysferlinopathy
Neuropathology and Applied Neurobiology, Vol.48(7), e12846
2022
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.
Details
- Title
- Identification of a novel heterozygous DYSF variant in a large family with a dominantly‐inherited dysferlinopathy
- Authors/Creators
- C. Folland (Author/Creator) - Harry Perkins Institute of Medical ResearchR. Johnsen (Author/Creator) - Murdoch UniversityA. Botero Gomez (Author/Creator)D. Trajanoski (Author/Creator) - Pathwest Laboratory MedicineM.R. Davis (Author/Creator) - Pathwest Laboratory MedicineU. Moore (Author/Creator) - The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust Newcastle upon Tyne United KingdomV. Straub (Author/Creator) - The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust Newcastle upon Tyne United KingdomR. Barresi (Author/Creator) - IRCCS San Camillo HospitalM. Guglieri (Author/Creator) - The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust Newcastle upon Tyne United KingdomH. Hayhurst (Author/Creator) - Newcastle upon Tyne Hospitals NHS Foundation TrustA.M. Schaefer (Author/Creator) - Newcastle upon Tyne Hospitals NHS Foundation TrustN.G. Laing (Author/Creator) - Harry Perkins Institute of Medical ResearchP.J. Lamont (Author/Creator) - Royal Perth HospitalG. Ravenscroft (Author/Creator) - Harry Perkins Institute of Medical Research
- Publication Details
- Neuropathology and Applied Neurobiology, Vol.48(7), e12846
- Publisher
- Wiley
- Identifiers
- 991005540856007891
- Copyright
- © 2022 British Neuropathological Society.
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics
- Language
- English
- Resource Type
- Journal article
UN Sustainable Development Goals (SDGs)
This output has contributed to the advancement of the following goals:
Source: InCites
Metrics
56 Record Views
InCites Highlights
These are selected metrics from InCites Benchmarking & Analytics tool, related to this output
- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.255 Musculoskeletal Disorders
- 1.255.628 Duchenne Muscular Dystrophy
- Web Of Science research areas
- Clinical Neurology
- Neurosciences
- Pathology
- ESI research areas
- Neuroscience & Behavior