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.

Congenital heart malformations are the most common type of defects found at birth. About 1% of infants are born with one or more heart defect on a yearly basis. Congenital Heart Disease (CHD) causes more deaths in the first year of life than any other congenital abnormality, and each year, nearly twice as many children die in the United States from CHD as from all forms of childhood cancers combined. Atrioventricular septal defects (AVSD) are congenital heart malformations affecting approximately 1 in 2000 live births. Babies born with an AVSD often require surgical intervention shortly after birth. However, even after successful surgery, these individuals typically have to deal with lifelong complications with the most common being a leaky mitral valve. In recent years the understanding of the molecular etiology and morphological mechanisms associated with the pathogenesis of AVSDs has significantly changed. Specifically, these studies have linked abnormal development of the Dorsal Mesenchymal Protrusion (DMP), a Second Heart Field-derived structure, to the development of this congenital defect. In this review we will be discuss some of the latest insights into the role of the DMP in the normal formation of the atrioventricular septal complex and in the pathogenesis of AVSDs.

We report a molecular cytogenetic characterization of 17p13.3 deletion syndrome by array comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH) and quantitative polymerase chain reaction (qPCR) in a fetus with lissencephaly, corpus callosum dysgenesis, ventriculomegaly, microcephaly, intrauterine growth restriction (IUGR), polyhydramnios and single umbilical artery. aCGH analysis revealed a 3.17-Mb deletion at 17p13.3, or arr [hg19] 17p13.3 (0-3,165,530)×1. The qPCR assays revealed a maternal origin of the deletion. Metaphase FISH analysis detected the absence of the LIS1 probe signal on the aberrant chromosome 17. The karyotype was 46,XX,del(17)(p13.3). We review the literature of chromosome 17p13.3 deletion syndrome with prenatal findings and diagnosis, and suggest that prenatal ultrasound detection of central nervous system anomalies such as lissencephaly, corpus callosum dysgenesis/agenesis, ventriculomegaly and microcephaly associated with IUGR, polyhydramnios, congenital heart defects, abdominal wall defects and renal abnormalities should include a differential diagnosis of chromosome 17p13.3 deletion syndrome.