MCF2 – Nervous System Disorder

Recent multi‐patient studies have identified candidate structural variant events involving a fusion of MCF2 with FGF13 in 4–5 distinct families (PMID:38746462) (PMID:40138663). Although these candidate events were detected in families affected by a nervous system disorder, there is minimal segregation evidence available. The genetic findings are based on analysis of unsolved rare disease cases using HiFi long‑read sequencing, and while the gene has been implicated in a subset of cases, the overall number of probands and detailed familial cosegregation studies are limited.

Complementary functional experiments provide moderate support for the gene’s involvement. Studies investigating alternative splicing of MCF2 (also known as DBL) have demonstrated differential guanine nucleotide exchange factor (GEF) activity, while mutagenesis of key residues in the Dbl homology domain revealed an impact on transformation potential (PMID:12445822) (PMID:10854437). Although these functional assessments reflect a mechanistic basis for pathogenicity through aberrant GEF activity, they do not fully overcome the limited genetic evidence provided by the candidate fusion events. Overall, the integration of genetic and functional data yields a limited, yet biologically plausible, association that may prove useful in guiding diagnostic decision‑making and further research.

References

• medRxiv • 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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