Rare De Novo Copy Number Variants in Patients with Congenital Pulmonary Atresia

Abstract

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.

Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome

“…The 22q11DS cohort was assessed for the rare CNVs reported in these non-syndromic CHD studies. The most commonly reported “rare” recurrent rearrangement in non-syndromic CHDs is a gain (Erdogan et al 2008; Geng et al 2014; Glessner et al 2014; Greenway et al 2009; Lalani et al 2013; Serra-Juhe et al 2012; Silversides et al 2012; Soemedi et al 2012a; Tomita-Mitchell et al 2012; Xie et al 2014) or loss (Christiansen et al 2004; Greenway et al 2009; Soemedi et al 2012a) of 1q21.1; interestingly, this 1q21.1 CNV was not detected in any of the 22q11DS subjects. One 22q11DS subject with TOF carried a deletion at 16p13.11 that encompassed MYH11 (MIM 160745) (Fig.…”

“…S5; Table S10), a known CHD risk gene (Zhu et al 2006). CNVs impacting MYH11 have been observed in several non-syndromic CHD studies (Lalani et al 2013; Soemedi et al 2012b; Tomita-Mitchell et al 2012; Xie et al 2014). The largest nonrecurrent rare CNV identified in the 22q11DS cohorts was a rare 5.3 Mb deletion at 18q11.2–12.1 that overlaps a 202 kb deletion reported by Soemedi et al (2012b); the heterozygous deletion included the gene CDH2 (MIM 114020), which is involved in Wnt-signaling (Fig.…”

Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot

“…Together, Camta2 and Nkx2-5 promote cardiac hypertrophy in mice (73). CAMTA2 was also identified as the likely candidate gene from a de novo CNV deletion at 17p13.2 in a patient with congenital pulmonary atresia (74). DLX6 encodes a homeobox protein involved with known role in cranial-facial morphogenesis.…”

Advances in molecular genetics for pulmonary atresia

“…Table 2 lists pathogenic and likely pathogenic copy number variants found in pulmonary atresia patients. Being widely considered as pathogenic, a 16p13.1 duplication was also reported in other kinds of CHD such as aortic dissections, tetralogy of Fallot, transposition of the great arteries, and hypoplastic left heart syndrome, 16,[18][19][20][21] as well as other extracardiac clinical features such as behavioural abnormalities, cognitive impairment, and skeletal manifestations. 20 This region contains 12 genes, including myosin heavy chain 11 (MYH11), whose mutations may cause non-syndromic thoracic aortic aneurysms and patent ductus arteriosus.…”