SOS2 – Noonan Syndrome

SOS2 encodes a RAS guanine nucleotide exchange factor and has been implicated in Noonan syndrome, an autosomal dominant RASopathy characterized by facial dysmorphism, congenital heart defects, and variable growth and developmental anomalies. Heterozygous SOS2 variants account for approximately 3% of Noonan syndrome cases, expanding the genetic spectrum beyond the classical SOS1, PTPN11, RAF1, and KRAS genes ([PMID:25795793]).

Genetic evidence includes rare, segregating or de novo missense variants identified in 2/50 Brazilian probands ([PMID:25795793]), five unrelated sporadic or familial cases with DH-domain mutations ([PMID:26173643]), and an independent cohort of 17 individuals carrying SOS2 variants ([PMID:32788663]). Key variants cluster at protein-interaction hotspots, exemplified by c.3275C>T (p.Pro1092Leu) ([PMID:25795793]). Segregation in two additional kindreds (American and Polish) supports autosomal dominant transmission.

Variant spectrum is dominated by missense changes within the Dbl homology domain (n = 4 hotspots) and nearby regulatory regions. No recurrent founder alleles have been established. Reported phenotypes align with classical Noonan syndrome, with notable prevalence of lymphatic complications in carriers of SOS2 variants.

Functional studies demonstrate that SOS2 mutations disrupt autoinhibitory contacts, leading to increased RAS–ERK pathway activation in cell-based assays and patient-derived fibroblasts ([PMID:26173643]). Mouse and cellular models show enhanced ERK phosphorylation and altered cell morphology consistent with RASopathies. Rescue experiments with MEK inhibitors normalize pathway hyperactivation, confirming gain-of-function mechanism.

Clinical phenotype includes short stature (HP:0004322), facial dysmorphism (HP:0000271), pulmonic stenosis (HP:0001642), hypertrophic cardiomyopathy (HP:0001639), and a high risk of lymphatic anomalies such as increased nuchal translucency (HP:0010880), chylothorax (HP:0010310), and lymphedema (HP:0001004) ([PMID:32788663]; [PMID:35979676]; [PMID:35770001]).

Integration of genetic and functional data warrants a Strong clinical validity classification for SOS2 in Noonan syndrome. Continued surveillance for genotype-phenotype correlations will refine risk assessment. Key take-home: Heterozygous SOS2 gain-of-function variants cause a recognizable Noonan syndrome subtype with cardiac and lymphatic involvement, informing diagnosis and potential targeted therapy.

References

• Journal of medical genetics • 2015 • Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. [PMID:25795793]
• Human mutation • 2015 • Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome. [PMID:26173643]
• European journal of human genetics : EJHG • 2021 • Variants of SOS2 are a rare cause of Noonan syndrome with particular predisposition for lymphatic complications. [PMID:32788663]
• American journal of medical genetics. Part A • 2022 • Lymphatic anomalies during lifetime in patients with Noonan syndrome: Retrospective cohort study. [PMID:35979676]
• Frontiers in genetics • 2022 • Cardiovascular Abnormalities and Gene Mutations in Children With Noonan Syndrome. [PMID:35770001]

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