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Published (Version of Record)CC BY-NC V4.0, Open Access
Journal article
Novel missense variants in CFL2 affect F-actin depolymerisation and expand the disease spectrum of CFL2-related myopathy
Human molecular genetics, Online ahead of print
2025
PMID: 40581737
Abstract
Cofilin-2, encoded by CFL2, is an actin-binding protein essential for regulating actin filament dynamics in skeletal muscle. Biallelic variants in CFL2 are associated with an ultra-rare, early-onset myopathy typically presenting as nemaline myopathy. Only 10 patients have been described to date from five unrelated families. Here, we describe two new cases from two unrelated families. The first proband presented clinically with rigid spine syndrome and a biopsy keeping with nemaline myopathy. The second proband presented with a relatively mild congenital myopathy which became rapidly progressive in the fourth decade, the muscle biopsy showed cytoplasmic bodies, internal nuclei and ringbinden. Exome and genome sequencing revealed three novel biallelic missense variants in CFL2, a homozygous c.115 T > G; p.(Cys39Gly) in the proband of Family 1, and bi-allelic heterozygous c.256G > A:(p.Asp86Asn), and c.283A > G (p.Lys95Glu) variants in the proband of Family 2. We characterised the effects of these substitutions using an in vitro F-actin depolymerisation assay and showed all three were associated with significantly reduced filamentous actin depolymerisation rates compared to the wildtype. Taken together, our findings are highly suggestive of a CFL2-related disease in these patients. Since CFL2-related myopathies are ultrarare, the application of ACMG/AMP guidelines and the diagnostic reportability of CFL2 variants identified in patients remains a challenge. The actin depolymerisation assay may be useful to elucidate the impact and pathogenicity of additional CFL2 variants and has the potential to guide variant classification in future.
Details
- Title
- Novel missense variants in CFL2 affect F-actin depolymerisation and expand the disease spectrum of CFL2-related myopathy
- Authors/Creators
- Lein N H Dofash - Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Verdun Street, Nedlands, Perth WA 6009, AustraliaChiara Folland - Harry Perkins Institute of Medical ResearchJason Dyke - Royal Perth HospitalEmna Farhat - Tunis UniversityMyriam Chaabouni - Tunis UniversityNajoua Miladi - Tunis El Manar UniversityMerrilee Needham - Fiona Stanley HospitalPhillipa J Lamont - Royal Perth HospitalCatherine Ashton - Royal Perth HospitalGianina Ravenscroft - Harry Perkins Institute of Medical Research
- Publication Details
- Human molecular genetics, Online ahead of print
- Publisher
- OXFORD UNIV PRESS
- Number of pages
- 9
- Identifiers
- 991005789548507891
- Copyright
- © The Author(s) 2025
- Murdoch Affiliation
- Health Futures Institute; Personalised Medicine Centre
- Language
- English
- Resource Type
- Journal article
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- Domestic collaboration
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- Citation topics
- 1 Clinical & Life Sciences
- 1.96 Cell Biology
- 1.96.492 Myosin
- Web Of Science research areas
- Biochemistry & Molecular Biology
- Genetics & Heredity
- ESI research areas
- Molecular Biology & Genetics