SHOC2 – Noonan syndrome-like disorder with loose anagen hair

SHOC2 encodes a scaffold protein facilitating RAS-MAPK signal transmission. Germline heterozygous mutations in SHOC2 underlie Noonan syndrome-like disorder with loose anagen hair (NSLAH), an autosomal dominant RASopathy characterized by craniofacial features, cardiac defects, developmental delay, and distinctive ectodermal anomalies (SHOC2; Noonan syndrome-like disorder with loose anagen hair).

Genetic studies have identified the recurrent missense variant c.4A>G (p.Ser2Gly) in 8 unrelated probands (PMID:20882035) and in a second case complicated by neuroblastoma (PMID:25846317), as well as three additional pathogenic variants reported in 8 other individuals (c.807_808delinsTT (p.Gln269_His270delinsHisTyr) (PMID:31059601); c.519G>A (p.Met173Ile) and p.Gln269Arg in six cases (PMID:35348676)). All variants occurred de novo, supporting an autosomal dominant inheritance.

The clinical phenotype of NSLAH is homogeneous among S2G carriers and expanded by additional variants, including short stature (HP:0004322), loose anagen hair (HP:0040169), macrocephaly, cardiac anomalies, and neurodevelopmental defects. Two S2G carriers developed early-onset neuroblastoma, suggesting a possible tumor predisposition (PMID:25846317).

Functional assays demonstrate that NSLAH-associated SHOC2 variants act via a gain-of-function mechanism: p.Ser2Gly induces aberrant N-myristoylation and plasma membrane localization leading to constitutive ERK1/2 activation (PMID:20882035; PMID:27466182). Structural and cellular studies of p.Gln269_His270delinsHisTyr confirm enhanced MRAS and PPP1CB binding with MAPK upregulation (PMID:31059601). A zebrafish shoc2 null model recapitulates key developmental defects, validating in vivo relevance (PMID:30329053).

No studies have reported loss-of-function or noncoding variants associated with NSLAH, and negative cancer screens argue against a major role of SHOC2 somatic mutations in pediatric malignancies.

In summary, SHOC2 meets ClinGen criteria for a Strong gene–disease association: multiple de novo gain-of-function missense variants in 16 unrelated individuals, consistent segregation, and concordant experimental evidence. Identification of SHOC2 mutations informs molecular diagnosis, enables management of cardiac and developmental features, and guides cancer surveillance. Key Take-home: SHOC2 gain-of-function variants are the definitive cause of NSLAH, and testing should be included in RASopathy panels for early diagnosis and tailored care.

References

• Journal of human genetics • 2010 • Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies PMID:20882035
• American journal of medical genetics. Part A • 2015 • Noonan syndrome-like disorder with loose anagen hair: a second case with neuroblastoma. PMID:25846317
• Human mutation • 2019 • Clinical and functional characterization of a novel RASopathy-causing SHOC2 mutation associated with prenatal-onset hypertrophic cardiomyopathy PMID:31059601
• Human molecular genetics • 2016 • SHOC2 subcellular shuttling requires the KEKE motif-rich region and N-terminal leucine-rich repeat domain and impacts on ERK signalling PMID:27466182
• Human molecular genetics • 2019 • Hematopoietic and neural crest defects in zebrafish shoc2 mutants: a novel vertebrate model for Noonan-like syndrome PMID:30329053
• Human molecular genetics • 2022 • Expanding the molecular spectrum of pathogenic SHOC2 variants underlying Mazzanti syndrome PMID:35348676

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