KRAS – Noonan syndrome

Noonan syndrome is an autosomal dominant RASopathy characterized by congenital heart defects, short stature, facial dysmorphism, and variable developmental delay. Germline missense mutations in KRAS account for approximately 2–5% of NS cases, with over 30 unrelated probands reported across multiple independent studies, including both de novo occurrences and familial transmissions ([PMID:16474405], [PMID:31219622]). This body of evidence spans case series, multi-patient cohorts, and functional concordance in cellular and animal models, warranting a Definitive ClinGen classification for KRAS–Noonan syndrome association.

Genetic evidence supports autosomal dominant inheritance with both de novo and vertical transmission patterns. Fifteen distinct missense variants—clustered around switch regions and the C-terminus—have been identified in 33 probands, including recurrent and family-specific alleles. Segregation has been demonstrated in three additional affected relatives across two families carrying p.Met72Leu and p.Lys147Glu variants ([PMID:22488932]). The variant spectrum is exclusively gain-of-function missense (e.g., c.458A>T (p.Asp153Val)), with no loss-of-function alleles reported, underscoring a consistent mechanistic theme.

Functional assays reveal that NS-associated KRAS mutants exhibit impaired GTP hydrolysis, increased GTP binding, and heightened downstream ERK phosphorylation in cell lines, phenotypes milder than classical oncogenic alleles but sufficient to perturb development ([PMID:16474405]). Morpholino knock-down and rescue experiments in zebrafish embryos expressing p.Asn116Ser demonstrate cardiac and craniofacial defects recapitulating human NS, confirming pathogenic hyperactivation of the RAS–MAPK pathway ([PMID:22302539]). These studies firmly establish a gain-of-function mechanism for KRAS in NS pathogenesis.

Phenotypic expansion includes craniosynostosis in ~10% of cases (p.Pro34Gln) and neuro-oncologic complications such as tenosynovial giant cell tumor (p.Gln22Arg), highlighting variable expressivity. Genotype-phenotype correlations suggest that variants in distinct KRAS domains may modulate risk for specific features, although overall clinical management remains guided by the core NS phenotype ([PMID:26249544]).

Diagnostic implications of these findings support inclusion of KRAS in multi-gene panels for NS, especially when PTPN11 and SOS1 mutations are absent. The consistent gain-of-function mechanism suggests potential for targeted MEK inhibition, although therapeutic utility requires careful evaluation of developmental timing and off-target effects.

Key Take-home: Germline KRAS gain-of-function mutations are a definitive, albeit rare, cause of autosomal dominant Noonan syndrome, with robust genetic and experimental evidence to inform diagnosis and mechanistic understanding.

References

• Nature Genetics • 2006 • Germline KRAS mutations cause Noonan syndrome PMID:16474405
• American Journal of Human Genetics • 2006 • Germline missense mutations affecting KRAS Isoform B are associated with a severe Noonan syndrome phenotype PMID:16773572
• American Journal of Medical Genetics Part A • 2012 • Characterization of a novel KRAS mutation identified in Noonan syndrome PMID:22302539
• American Journal of Medical Genetics Part A • 2015 • Craniosynostosis and Noonan syndrome with KRAS mutations: Expanding the phenotype with a case report and review of the literature PMID:26249544
• Annals of Pediatric Endocrinology & Metabolism • 2017 • An atypical case of Noonan syndrome with KRAS mutation diagnosed by targeted exome sequencing PMID:29025208

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