Somatic mosaicism for an HRAS mutation causes Costello syndrome

Abstract

De novo heterozygous HRAS point mutations have been reported in more than 81 patients with Costello syndrome (CS), but genotype/phenotype correlation remains incomplete because the majority of patients share a common mutation, G12S, seen in 65/81 (80%). Somatic HRAS mutations have previously been identified in solid tumors, and mutation hot spots related to a gain-of-function effect of the gene product are known. The germline mutations causing CS occur at these hot spots and convey a gain-of-function effect, thus accounting for the greatly increased cancer risk. Diagnostic testing for HRAS mutations is now available and the identification of a mutation in a patient with consistent clinical findings confirms a diagnosis of CS. It is not clear yet if the absence of an HRAS mutation precludes a diagnosis of CS. Because there is a significant overlap in the clinical findings of Costello, cardio-facio-cutaneous, and Noonan syndromes, diagnostic uncertainty remains in patients lacking an HRAS mutation. We report here on a female with findings suggestive of CS in whom mutation analysis performed with standard techniques on white blood cell derived DNA did not show an HRAS mutation. However, analysis of DNA derived from three independently collected buccal swabs showed a sequence change qualitatively consistent with the G12S mutation. Allelic quantitation showed the presence of the mutation in approximately 25%-30% of the sampled buccal cells. In this patient, standard technology failed to identify the disease causing mutation on DNA derived from a blood sample, highlighting the potential pitfalls in the interpretation of negative mutation studies. This is the first reported CS patient mosaic for the common HRAS mutation, likely due to a somatic mutation occurring very early in fetal development.

Progesterone and AdipoQ Receptor 11 Links Ras Signaling to Cardiac Development in Zebrafish

“…Activating mutations of the tyrosine phosphatase SHP2, HRas, B-Raf, and MEK1/2 were found in Noonan syndrome, Costello syndrome, and cardiofaciocutaneous syndrome. 10,[41][42][43][44][45] The common features of these syndromes, include hypertrophic cardiomyopathy, electrophysiological abnormalities, and septal defects. 46 Although a gain-of-function mutation of Ras signaling is believed to be the underlying mechanism for congenital heart disease, emerging evidence from clinical and genetic studies have revealed that downregulation of Ras/ERK singling is also associated with cardiac defects during development.…”

Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations

“…Atypical findings included microcephaly, streaky areas of skin hypo-and hyperpigmentation, and normal menarche with subsequent regular menses. 44 Somatic mosaicism was seen in a father who showed a patchy distribution of skin findings suggestive of Costello syndrome and who transmitted the p.Gly12Ser change to his son with typical Costello syndrome. 13 Mosaicism for the p.Gly12Ser mutation was noted in an individual with a typical presentation including apparent cutis laxa.…”

“…14 As may be expected in an autosomal dominant trait, somatic mosaicism can thus be associated with a range of findings including patchy or segmental distribution, typical phenotypic presentation, and transmission to offspring and recurrence in siblings. 44 …”

What’s new in the neuro-cardio-facial-cutaneous syndromes?

“…Later reports confirmed the presence of HRAS codon 12 and 13 mutations in 85-90% of Costello syndrome patients with G12S being the most prevalent mutation and G12A the second most prevalent [14,17,26]. One report described somatic mosaicism for an HRAS codon 12 mutation [19]. As mentioned before, these mutations derange RAS GTP-ase activity and cause activation of the RAS MAPK pathway.…”