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BackgroundOngoing studies using genomic microarrays and next-generation sequencing have demonstrated that the genetic contributions to cardiovascular diseases have been significantly ignored in the past. The aim of this study was to identify rare copy number variants in individuals with congenital pulmonary atresia (PA).Methods and ResultsBased on the hypothesis that rare structural variants encompassing key genes play an important role in heart development in PA patients, we performed high-resolution genome-wide microarrays for copy number variations (CNVs) in 82 PA patient-parent trios and 189 controls with an Illumina SNP array platform. CNVs were identified in 17/82 patients (20.7%), and eight of these CNVs (9.8%) are considered potentially pathogenic. Five de novo CNVs occurred at two known congenital heart disease (CHD) loci (16p13.1 and 22q11.2). Two de novo CNVs that may affect folate and vitamin B12 metabolism were identified for the first time. A de novo 1-Mb deletion at 17p13.2 may represent a rare genomic disorder that involves mild intellectual disability and associated facial features.ConclusionsRare CNVs contribute to the pathogenesis of PA (9.8%), suggesting that the causes of PA are heterogeneous and pleiotropic. Together with previous data from animal models, our results might help identify a link between CHD and folate-mediated one-carbon metabolism (FOCM). With the accumulation of high-resolution SNP array data, these previously undescribed rare CNVs may help reveal critical gene(s) in CHD and may provide novel insights about CHD pathogenesis.

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.