Atrioventricular septal defects (AVSDs) account for approximately 5% of all congenital heart disease (CHD). About half of AVSDs are diagnosed in cases with trisomy 21 (Down's syndrome, DS). However, many AVSDs occur sporadically and manifest as non-syndromic. The pathogenesis is complex and has not yet been fully elucidated. In the present study, we applied two advanced applications of next-generation sequencing (NGS) to explore the genetic variations in families with fetal non-syndromic AVSDs. Our study was mainly divided into two steps: (1) low-pass whole-genome sequencing (WGS) was used to detect the genome-wide copy number variations (CNVs) for included subjects; (2) whole-exome sequencing (WES) was used to detect the gene mutations for the subjects without AVSD-associated CNVs. A total of 17 heterozygous de novo CNVs and 19 heterozygous de novo gene mutations were selected, and 15 candidate genes were involved in these variations. Among these heterozygous de novo variations, most have potential pathogenicity for AVSDs, but the others require further investigation to confirm their pathogenicity. Our study not only shows the genetic diversity and the etiological complexity of AVSDs but also shows the rationality and practicability of this sequential genetic detection and analysis strategy.
Keywords: AVSD; copy number variation; gene mutation; whole-exome sequencing; whole-genome sequencing.
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