Genotype and phenotype spectrum of NRAS germline variants

Abstract

RASopathies comprise a group of disorders clinically characterized by short stature, heart defects, facial dysmorphism, and varying degrees of intellectual disability and cancer predisposition. They are caused by germline variants in genes encoding key components or modulators of the highly conserved RAS-MAPK signalling pathway that lead to dysregulation of cell signal transmission. 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). A small number of RASopathy cases with disease-causing germline NRAS alterations have been reported. Affected individuals exhibited features fitting Noonan syndrome, and the observed germline variants differed from the typical oncogenic NRAS changes occurring as somatic events in tumours. Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS. Importantly, four of them harbored missense changes affecting Gly12, which was previously described to occur exclusively in cancer. The phenotype in our cohort was variable but well within the RASopathy spectrum. Further, one of the patients (c.35G>A; p.(Gly12Asp)) had a myeloproliferative disorder, and one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour. With this report, we expand the genotype and phenotype spectrum of RASopathy-associated germline NRAS variants and provide evidence that NRAS variants do not spare the cancer-associated mutation hotspots.

Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome

“…Consistent with the collected functional data, p.Gln72Leu (analogous to p.Gln61Leu in HRAS, NRAS, and KRAS) is a strong activating mutation and has not been observed to occur as a germline event in HRAS, KRAS, or NRAS. Similar differences in the biological and phenotypic consequences have previously been reported for HRAS, NRAS, and KRAS, [12][13][14]30,31,[46][47][48][49][50][51][52][53] including the positions corresponding to the presently identified RRAS2 mutations. The genotype-phenotype correlations in HRAS are illustrative and correlate well with the present findings: while p.Ala59Thr has been associated with Costello syndrome and p.Gly12Val has been reported with severe expression of Costello syndrome, 46 p.Gln61Leu and other changes at this codon have only been reported as somatic events in cancer (Table S1).…”

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

“…For example, SOS2 ‐NS appeared to be markedly associated with a cutaneous phenotype very close to that observed with SOS1 ‐NS, characterized by a high prevalence of keratinization disorders including KP and UO . In contrast, we could not confirm the high prevalence of MMN in NRAS ‐NS as previously reported in over one‐third of patients . For the other NS genotypes, including mutations of LZTR1 , CBL , RIT1 and KRAS , no conclusion could be drawn from our study owing to the low number of patients and the lack of significant dermatological phenotypes reported in the literature.…”

De novomutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay

“…Associated features include neurocognitive impairment, craniofacial dysmorphology, anomalies of the cardiovascular and musculoskeletal systems, cutaneous lesions, and increased risk of tumor formation [6]. For example, variation in HRAS is associated with Costello Syndrome (MIM:218040) and Noonan Syndrome (MIM:609942), variation in KRAS is associated with Cardiofaciocutaneous syndromes (MIM:615278), and variation in NRAS has been observed in probands with RASopathy-associated phenotypes [7].…”