Whole exome sequencing (WES) revealed a previously well established, disease-causing heterozygous likely pathogenic variant in the Harvey rat sarcoma viral oncogene homolog (HRAS)-gene (c.35G > C, p. rs104894230" genes_norm="3265">G12A, rs104894230), which implied the clinical diagnosis of Costello syndrome (CS; OMIM#190020.0004).
To examine the mechanisms of energy reprogramming by HRAS activation in vivo, we generated knock-in mice expressing a heterozygous Hras G12S mutation (Hras<sup>G12S/+</sup> mice) as a mouse model of Costello syndrome.
Somatic KRAS mutations are often detected in patients with solid and non-solid tumors, whereas germline KRAS mutations are implicated in patients with the Noonan syndrome, cardio-facio-cutaneous (CFC) syndrome and Costello syndrome.
The clinical characteristics of the Costello syndrome individuals harboring rarer HRAS mutations are less understood, due to the small number of reported cases.
Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants) to Noonan and Cardiofaciocutaneous syndromes (KRAS variants).
Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants) to Noonan and Cardiofaciocutaneous syndromes (KRAS variants).
Patients with the HRAS mutation c.173C>T (p.T58I) might go undiagnosed because of the milder phenotype compared with other mutations causing Costello syndrome.
Paternal uniparental disomy with segmental loss of heterozygosity of chromosome 11 are hallmark characteristics of syndromic and sporadic embryonal rhabdomyosarcoma.
Costello syndrome is a type of RASopathy mapped to HRAS gene in chromosome 11, characterized by prenatal overgrowth, postnatal failure to thrive, classic facial gestalt and multisystem involvement including cardiomyopathy and intellectual disability.