SOS1 – Cardiofaciocutaneous Syndrome

Son of Sevenless 1 (SOS1) encodes a RAS guanine nucleotide exchange factor that regulates RAS/MAPK signaling downstream of receptor tyrosine kinases. Heterozygous gain-of-function SOS1 variants are implicated in RASopathies, including cardiofaciocutaneous (CFC) syndrome (MONDO:0015280), an autosomal dominant disorder characterised by ectodermal anomalies, intellectual disability, congenital heart defects and short stature (HP:0000271, HP:0001249, HP:0001627, HP:0004322).

Clinical Validity

Associations between SOS1 and CFC have been observed in 4 unrelated probands: 1 of 31 CFC patients harboured a SOS1 E433K variant (PMID:18456719) and 3 of 30 CFC patients carried distinct SOS1 missense changes (PMID:18651097). Although no multigenerational CFC pedigrees have been reported, functional concordance across cellular and animal studies supports pathogenicity. On this basis, the SOS1–CFC association is categorised as Moderate.

Genetic Evidence

Inheritance is autosomal dominant with exclusively missense variants disrupting autoinhibitory domains. Four independent CFC cases exhibit SOS1 missense alleles with no reported loss-of-function or splice variants. A representative change is c.1297G>A (p.Glu433Lys), affecting the histone-like domain and observed in a patient with CFC (PMID:18456719). SOS1 mutations account for ~3%–4% of CFC cohorts lacking mutations in BRAF, MEK1/2 or KRAS.

Functional Evidence

SOS1 CFC-associated variants act via gain-of-function. The T158A mutant enhances ERK1/2 phosphorylation kinetics and alters AKT/p70S6K signaling under EGF stimulation in transfected 293T cells, indicating dysregulated RAS/MAPK and PI3K/Akt pathways (PMID:23528009). Mouse Sos1 null fibroblasts and embryos display impaired ERK activation and cardiovascular defects, confirming in vivo requirement of Sos1 in EGFR–RAS signaling (PMID:9030684).

Integration & Clinical Utility

Collectively, SOS1 missense variants confer CFC syndrome through RAS pathway hyperactivation, supported by genetic and functional concordance. Additional rare alleles and modifier loci may exist but exceed current evidence caps. Key Take-home: inclusion of SOS1 in diagnostic panels for CFC syndrome enhances molecular diagnosis, guides prognostic stratification, and informs potential RAS-targeted therapies.

References

• Journal of medical genetics • 2008 • Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders. PMID:18456719
• Journal of human genetics • 2008 • Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome. PMID:18651097
• Journal of receptor and signal transduction research • 2013 • A novel SOS1 mutation in Costello/CFC syndrome affects signaling in both RAS and PI3K pathways. PMID:23528009
• Genes & development • 1997 • Mutation in Sos1 dominantly enhances a weak allele of the EGFR, demonstrating a requirement for Sos1 in EGFR signaling and development. PMID:9030684

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