HRAS – Costello syndrome

Costello syndrome is an autosomal dominant RASopathy caused by germline gain-of-function variants in the HRAS proto-oncogene ([PMID:16372351]). Patients present with prenatal overgrowth, postnatal failure to thrive, coarse facial features, skin laxity, cardiac abnormalities, intellectual disability and a predisposition to benign and malignant tumors. The diagnosis may be challenging in neonates due to overlap with sequelae of prematurity.

HRAS-related Costello syndrome follows an autosomal dominant inheritance with the majority of cases arising de novo. A recent meta-analysis identified 621 affected individuals ([PMID:36966234]) with >90% harboring the recurrent p.Gly12Ser substitution. Additional probands carry missense changes at Gly12, Gly13 and rare codons S89, T58, A59, A146, supporting a strong genetic contribution by multiple variant classes.

The variant spectrum is dominated by c.34G>A (p.Gly12Ser) but includes c.35G>C (p.Gly12Ala), c.35_36GC>AA (p.Gly12Glu), c.37G>T (p.Gly13Cys) and noncanonical substitutions such as c.266C>G (p.Ser89Cys) and c.436G>C (p.Ala146Pro) ([PMID:22821884]; [PMID:28328122]). Mosaicism is documented, including paternal somatic mosaic transmission of c.34G>A ([PMID:19206176]) and maternal germline mosaic recurrence in siblings ([PMID:21834037]).

Segregation analysis revealed three additional affected relatives across mosaic pedigrees, confirming variant segregation in non-sporadic cases. Parental origin studies show a paternal bias in de novo events ([PMID:17054105]). The high de novo rate and mosaic transmissions underscore the importance of parental testing and counseling.

Functional assays of HRAS mutants demonstrate impaired intrinsic GTP hydrolysis, GAP insensitivity, elevated RAF-MEK-ERK and PI3K-AKT signaling, and induction of oncogene-induced senescence in fibroblasts ([PMID:2199064]; [PMID:21850009]). Cellular models including iPSC-derived cardiomyocytes recapitulate multifocal atrial tachycardia driven by HRASG12 variants ([PMID:38415356]). Duplication and noncanonical mutants exhibit distinct signaling dynamics correlating with attenuated phenotypes ([PMID:23335589]; [PMID:22821884]).

Rare attenuated alleles (e.g., p.Ser89Cys, p.Ala59Gly) show reduced signaling output and milder clinical courses, highlighting genotype-phenotype variability. No compelling evidence disputes the HRAS–Costello syndrome association.

Collectively, >600 de novo HRAS variants, familial mosaic transmissions, and concordant functional data establish a definitive gene–disease relationship. HRAS mutation analysis is essential for diagnostic confirmation, prognostic assessment, surveillance of cardiac and oncologic complications, and informed genetic counseling.

References

• American journal of medical genetics. Part A • 2006 • HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy PMID:16372351
• Human mutation • 2007 • Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome PMID:17054105
• American journal of medical genetics. Part A • 2009 • Male-to-male transmission of Costello syndrome: G12S HRAS germline mutation inherited from a father with somatic mosaicism PMID:19206176
• PLoS genetics • 2016 • The Splicing Efficiency of Activating HRAS Mutations Can Determine Costello Syndrome Phenotype and Frequency in Cancer PMID:27195699
• Human molecular genetics • 2013 • Functional analysis of a duplication (p.E63_D69dup) in the switch II region of HRAS: new aspects of the molecular pathogenesis underlying Costello syndrome PMID:23335589
• Circulation. Arrhythmia and electrophysiology • 2024 • HRAS-Mutant Cardiomyocyte Model of Multifocal Atrial Tachycardia PMID:38415356

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