BRAF – Cardio-facio-cutaneous Syndrome

Cardio-facio-cutaneous (CFC) syndrome is an autosomal dominant RASopathy characterized by distinctive craniofacial dysmorphism, congenital heart defects, ectodermal anomalies, growth delay, hypotonia, and intellectual disability. Heterozygous de novo missense mutations in BRAF, encoding a RAF kinase in the MAPK pathway, have been identified in the majority of molecularly confirmed CFC cases, establishing BRAF as the principal gene for this disorder.

Genetic screening of 23 individuals demonstrated that ~75% of CFC probands harbor BRAF variants, predominantly clustering in the kinase domain ([PMID:16439621]). In a larger cohort of 138 patients, BRAF mutations were present in 90 individuals, with most alterations arising de novo ([PMID:35524774]). A sibling pair with the recurrent c.770A>G (p.Gln257Arg) variant illustrated rare germline mosaicism ([PMID:29704308]). Overall, more than 90 unrelated probands with heterozygous BRAF mutations support a definitive gene–disease relationship.

The variant spectrum comprises over 30 distinct missense changes, including the critical activation-loop substitution c.1799T>G (p.Val600Gly) ([PMID:20735442]), as well as other kinase-impairing and –activating alleles. No loss-of-function truncating variants have been implicated, consistent with a gain-of-function mechanism.

Functional assays confirm that CFC-associated BRAF mutants exhibit increased kinase activity and downstream MEK/ERK phosphorylation relative to wild-type, although typically less potent than the oncogenic p.Val600Glu variant ([PMID:18413255]). Patient-derived induced pluripotent stem cells recapitulate early developmental defects, which are rescued by pathway inhibition, further validating pathogenicity ([PMID:25639853]).

Clinical heterogeneity is notable: patients with different BRAF alleles present variable cardiac phenotypes, neurodevelopmental outcomes, and ectodermal features. However, de novo occurrence, consistent functional gain-of-function, and phenotypic concordance across cohorts underscore a definitive association.

Key Take-home: BRAF heterozygous gain-of-function mutations cause CFC syndrome via MAPK pathway hyperactivation, enabling molecular diagnosis, genetic counseling, and targeted therapeutic exploration.

References

• Science • 2006 • Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. PMID:16439621
• Nature Genetics • 2006 • Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. PMID:16474404
• Methods in enzymology • 2008 • Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome. PMID:18413255
• Stem Cells • 2015 • Enhanced SMAD1 Signaling Contributes to Impairments of Early Development in CFC-iPSCs. PMID:25639853
• American Journal of Medical Genetics Part A • 2018 • A sibling pair with cardiofaciocutaneous syndrome (CFC) secondary to BRAF mutation with unaffected parents—the first cases of gonadal mosaicism in CFC? PMID:29704308
• Clinical Genetics • 2011 • Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome. PMID:20735442

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