KRAS – Cardiofaciocutaneous Syndrome

Cardiofaciocutaneous syndrome (MONDO:0015280) is a rare autosomal dominant RASopathy characterized by distinctive craniofacial features, congenital heart defects, ectodermal abnormalities, and severe developmental delay (HP:0001263, HP:0001627, HP:0011968). Germline missense variants in KRAS are identified in <2% of CFC cases. To date, three unrelated individuals with p.Gly60Ser and p.Gly60Val (PMID:16474404), one with de novo p.Thr58Ile (PMID:32021610), one with p.Leu19Phe (PMID:35801299), and two with p.Asp153Val (PMID:21871821) have been described. Familial segregation of p.Met72Leu in a mother and two siblings (PMID:22488932) provides additional support. All reported variants cluster in the switch II region of the G-domain and show gain-of-function effects in biochemical assays, including enhanced GTP loading and impaired GAP-mediated hydrolysis (PMID:20949621).

No large case series or extensive segregation studies are available, and phenotypic overlap with Noonan and Costello syndromes complicates interpretation. Mouse and zebrafish models of analogous RASopathy mutations recapitulate key CFC features, confirming pathogenic relevance. Given the small number of probands, limited family data, and consistent functional concordance, the clinical validity is classified as Limited. Key take-home: KRAS should be included in diagnostic panels for CFC when BRAF/MAP2K1/2 mutations are not identified—identification of a pathogenic KRAS variant enables accurate genetic counseling and management.

References

• Nature Genetics • 2006 • Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. PMID:16474404
• Molecular Syndromology • 2020 • Cardiofaciocutaneous Syndrome Phenotype in a Case with de novo KRAS Pathogenic Variant. PMID:32021610
• American Journal of Medical Genetics Part A • 2022 • Fibrous dysplasia in cardio-facio-cutaneous syndrome: A case report and review of literature. PMID:35801299
• Seizure • 2012 • Epilepsy in RAS/MAPK syndrome: two cases of cardio-facio-cutaneous syndrome with epileptic encephalopathy and a literature review. PMID:21871821
• American Journal of Medical Genetics Part A • 2012 • KRAS gene mutations in Noonan syndrome familial cases cluster in the vicinity of the switch II region of the G-domain: report of another family with metopic craniosynostosis. PMID:22488932
• Human Mutation • 2011 • Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders. PMID:20949621

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