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CFL2 and Myofibrillar Myopathy

In a consanguineous family, a novel homozygous missense variant, c.19G>A (p.Val7Met) in CFL2 was identified in two affected siblings, presenting with congenital myopathy that exhibits overlapping features of both nemaline and myofibrillar myopathy (PMID:22560515). This case report provides the sole direct genetic evidence linking CFL2 to a phenotype that includes myofibrillar myopathy (MONDO_0018943). However, additional studies in candidate gene screens, such as one conducted in Warmblood horses with myofibrillar myopathy, did not detect a significant association between variants in CFL2 and the disease phenotype (PMID:32453872).

Functional data from in vitro assays and animal models further support the pathogenic role of CFL2 in muscle function. For instance, a knockin mouse model recapitulated a severe myopathic phenotype accompanied by aberrant splicing, thereby providing mechanistic insights into how CFL2 dysfunction may disrupt actin regulation (PMID:32160286). Additionally, biochemical studies have demonstrated that CFL2 is essential for proper actin filament dynamics in regenerating muscle (PMID:11422377). In summary, while functional evidence is moderately supportive and suggests a plausible disease mechanism, the limited number of unrelated probands and conflicting candidate gene data impose caution. Key take‑home: CFL2 analysis should be integrated into diagnostic pipelines for patients with overlapping myopathic features, but further studies are needed to solidify its role in myofibrillar myopathy.

References

  • Neuromuscular disorders : NMD • 2012 • Congenital myopathy caused by a novel missense mutation in the CFL2 gene PMID:22560515
  • Equine veterinary journal • 2021 • Candidate gene expression and coding sequence variants in Warmblood horses with myofibrillar myopathy PMID:32453872
  • European journal of biochemistry • 2001 • Characterization of human muscle type cofilin (CFL2) in normal and regenerating muscle PMID:11422377
  • Human molecular genetics • 2020 • Knockin mouse model of the human CFL2 p.A35T mutation results in a unique splicing defect and severe myopathy phenotype PMID:32160286

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Evidence is limited to a single family involving 2 probands with overlapping myopathic features (PMID:22560515) and is counterbalanced by negative findings in a multi‐patient candidate gene study (PMID:32453872).

Genetic Evidence

Limited

The identification of a novel homozygous missense variant, c.19G>A (p.Val7Met), in 2 siblings from a consanguineous family provides limited but direct genetic support (PMID:22560515).

Functional Evidence

Moderate

Functional assays, including a knockin mouse model that demonstrated disrupted CFL2 function and alternative splicing (PMID:32160286), as well as in vitro studies of actin regulation (PMID:11422377), provide moderate support for its role in muscle pathology.