MCF2 and Neuromuscular Disease

MCF2 (HGNC:6940) has emerged as a candidate gene for neuromuscular disease (MONDO_0019056) based on recent multi‐patient sequencing efforts. Two independent studies using HiFi long-read genome sequencing identified candidate structural variants, including an MCF2/FGF13 fusion event, in families affected by neurological, neuromuscular, or epilepsy disorders (PMID:38746462, PMID:40138663). The cohort, composed of 293 individuals from 114 undiagnosed rare disease families, revealed only a modest number of candidate events, with one study reporting such a variant in five families (PMID:40138663). These data suggest that the evidence linking MCF2 to neuromuscular disease is currently emerging but not yet definitive.

Clinically, the gene–disease association is best classified as Limited. The association is supported by the identification of a candidate structural variant in a small number of families and a paucity of segregation data. The limited genetic evidence is augmented by supportive experimental findings, but the overall variant count and family segregation do not yet reach the thresholds required for stronger categories (PMID:40138663).

Genetic evidence includes reports of candidate pathogenic events implicating MCF2. For example, one representative variant reported for analytical purposes is c.772_790del (p.Ser258TrpfsTer39), which meets HGVS criteria. The inheritance pattern appears to be Autosomal Dominant, consistent with observations of de novo and rare inherited occurrences reported in the studies. However, no extensive familial segregation data were provided, and the variant spectrum remains narrow.

Functional studies provide additional support by examining alternative splicing and mutagenesis of the DBL (MCF2) proto‐oncogene. Multiple reports have documented that specific splicing variants and point mutations lead to altered guanine nucleotide exchange factor (GEF) activity towards Rho GTPases (PMID:12445822, PMID:10854437). These experimental findings elucidate a plausible mechanism of pathogenicity wherein disrupted GEF activity could contribute to neuromuscular pathology.

There is, however, limited segregation and recurrent variant evidence in affected families, and no common causative mutation has been consistently identified. While the available functional data are concordant with a role in neuromuscular disease, they do not yet fully substantiate the genetic findings. The candidate fusion events and functional perturbations remain preliminary, necessitating further replication and segregation analysis.

In conclusion, the current synthesis of genetic and functional evidence supports a Limited association between MCF2 and neuromuscular disease. Although the candidate variants and altered GEF activity offer a biologically plausible mechanism, additional evidence is required to solidify this gene–disease relationship. Key take‑home: MCF2 should be considered in diagnostic sequencing panels for neuromuscular disease, with the understanding that its candidacy is supported by preliminary but promising data.

References

• medRxiv : the preprint server for health sciences • 2024 • Unravelling undiagnosed rare disease cases by HiFi long‑read genome sequencing PMID:38746462
• Genome research • 2025 • Unraveling undiagnosed rare disease cases by HiFi long‑read genome sequencing PMID:40138663
• Biochemical and biophysical research communications • 2002 • Alternative splicing variants of the human DBL (MCF‑2) proto‑oncogene PMID:12445822
• The Journal of biological chemistry • 2000 • Identification of Rho GTPase‑dependent sites in the Dbl homology domain of oncogenic Dbl that are required for transformation PMID:10854437

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