Rare de novo copy number variants in patients with congenital pulmonary atresia.
BACKGROUND
Ongoing 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).


RESULTS
Based 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.


CONCLUSIONS
Rare 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.
Department of Cardiothoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
Li
L
Xie
Department of Cardiothoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
Jin-Lan
JL
Chen
Department of Cardiothoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
Wei-Zhi
WZ
Zhang
Department of Cardiothoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
Shou-Zheng
SZ
Wang
Department of Cardiothoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
Tian-Li
TL
Zhao
Department of Cardiothoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
Can
C
Huang
Department of Cardiothoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China; The Clinical Center for Gene Diagnosis and Therapy of the State Key Laboratory of Medical Genetics, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
Jian
J
Wang
Department of Cardiothoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China; The Clinical Center for Gene Diagnosis and Therapy of the State Key Laboratory of Medical Genetics, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
Jin-Fu
JF
Yang
Department of Cardiothoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China; The Clinical Center for Gene Diagnosis and Therapy of the State Key Laboratory of Medical Genetics, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
Yi-Feng
YF
Yang
Department of Cardiothoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China; The Clinical Center for Gene Diagnosis and Therapy of the State Key Laboratory of Medical Genetics, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
Zhi-Ping
ZP
Tan
D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002885:Chromosomes, Human, Pair 16; D002886:Chromosomes, Human, Pair 17; D002892:Chromosomes, Human, Pair 22; D056915:DNA Copy Number Variations; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006330:Heart Defects, Congenital / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D018633:Pulmonary Atresia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D014463:Ultrasonography; D014805:Vitamin B 12 / Q000378:metabolism
D005492:Folic Acid; D014805:Vitamin B 12