title: Rare copy number variations containing genes involved in RASopathies: deletion of SHOC2 and duplication of PTPN11.
abstract: BACKGROUND
  RASopathies 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.
  
  
  RESULTS
  In 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Department of Cardiothoracic Surgery, the 2nd Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Jin-Lan
authors.initials: JL
authors.lastname: Chen
authors.affiliation: Department of Gynecology and Obstetrics, Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Cardiothoracic Surgery, the 2nd Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Tian-Li
authors.initials: TL
authors.lastname: Zhao
authors.affiliation: Department of Cardiothoracic Surgery, the 2nd Xiangya Hospital of Central South University, Changsha, China.|Clinical Center for Gene Diagnosis and Therapy of State Key Laboratory of Medical Genetics, the Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cardiothoracic Surgery, the 2nd Xiangya Hospital of Central South University, Changsha, China.|Clinical Center for Gene Diagnosis and Therapy of State Key Laboratory of Medical Genetics, the Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Yi-Feng
authors.initials: YF
authors.lastname: Yang
authors.affiliation: Department of Cardiothoracic Surgery, the 2nd Xiangya Hospital of Central South University, Changsha, China.|Clinical Center for Gene Diagnosis and Therapy of State Key Laboratory of Medical Genetics, the Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Tan
keywords: 10q25.2 deletion; 12q24 duplication; CNV; Congenital heart defect; Copy number variation; Noonan syndrome; PTPN11; RASopathy; SHOC2
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