Rare copy number variations containing genes involved in RASopathies: deletion of SHOC2 and duplication of PTPN11

Abstract

BackgroundRASopathies are a group of disorders related to Noonan syndrome that with dysregulated RAS-mitogen-activated protein kinase (MAPK) signaling pathway. Noonan syndrome (NS, OMIM# 163950) is a both phenotypically and genotypically variable disorder. We and other researchers have demonstrated that copy number variations underlie a small percentage of patients with RASopathies.ResultsIn a cohort of 12 clinically characterized patients with congenital heart defect (CHD) and features suggestive of Noonan syndrome or Noonan like syndrome without known causative gene mutation, we performed an Illumina SNP-array analysis to identify the pathogenic copy number variations (Human660W-Quad Chip, Beadstation Scanner and GenomeStudio V2011 software).We identifed two rare copy number variations harboring genes involved in RAS- MAPK signaling pathway of RASopathy. One is a 24 Mb duplication of 12q24.1-24.3 containing PTPN11 and the other is a 183 kb deletion of 10q25.2 including SHOC2. The SNP-array results were further validated by quantitative PCR (qPCR). This is might be the first report suggesting that haploinsufficiency of SHOC2 can result in a RASopathy-like phenotype.ConclusionsOur findings provide additional support that copy number variations containing disease-causing genes of RAS/MAPK pathway play a minor role in RASopathies or related disorders. We recommend the use of microarrays in Noonan syndrome like patients without identified mutations in the causative genes.

Rare variants inSOS2andLZTR1are associated with Noonan syndrome

“…Still, 15%–20% of the molecular basis of NS remains unexplained. Copy number variations encompassing the locus of one of the known genes associated with NS have been rarely reported27 and could account for a very small amount of the NS unknown aetiology. Alternatively, it remains to be investigated whether digenic inheritance could also play a role in NS aetiology, in which variants in two or more genes of the RAS/MAPK pathway would be required to overcome a threshold of increased ERK signalling, and consequently manifestation of the NS phenotype.…”

A de novo 1q22q23.1 Interstitial Microdeletion in a Girl with Intellectual Disability and Multiple Congenital Anomalies Including Congenital Heart Defect

“…It has been shown that different pathogenic variants in the RIT1 gene cause autosomal dominant Noonan syndrome through a gain-of-function mechanism resulting in increased RAS/MAPK signaling [Bertola et al, 2014;Gos et al, 2014;Milosavljević et al, 2016;Yaoita et al, 2016]. Recent reports have demonstrated that copy number variations containing disease-causing genes of RAS/MAPK pathway may be a pathogenetic mechanism for the etiology of RASopathies or related disorders [Graham et al, 2009;Luo et al, 2012;Chen et al, 2014]. Although our patient had no typical facial gestalt of Noonan syndrome and presented with atypical anomalies, such as cleft palate and hypoplastic corpus callosum, the RIT1 gene remains one of the candidate genes for her phenotype.…”

Expansion of the RASopathies

“…In each of these cases, gene duplication is thought to result in increased dosage of SHP2 which has the equivalent effect as the common gain of function mutation in PTPN11 associated with NS. In addition, rare chromosomal duplications associated with SHOC2 in a NS patient [56], and RAF1 and MAP2K2 in patients with mild RASopathy spectrum phenotypes have been reported [57, 58]. Chromosomal deletions have also been reported to be associated with a RASopathy phenotype.…”