Low-coverage whole-genome sequencing and target-region capture sequencing in fetal congenital heart disease

Abstract

Objective To explore the relationship between genetic phenotypes and clinical characteristics of fetal congenital heart disease(CHD) using low-coverage whole-genome sequencing and target sequencing. Methods Tissue specimens of 62 fetuses with CHD diagnosed by fetal echocardiography and confirmed by post-mortem autopsy from September 2012 to June 2015 were selected from the fetal cardiac malformation database of the Consultation Center of Maternal-Fetal Medicine in Fetal Heart Diseases, Beijing Anzhen Hospital, and classified according to the sectional embryology classification method. Low-coverage whole-genome sequencing and target sequencing were performed to detect chromosomal deletions or duplications and single nucleotide variation and small insertion/deletion fragment of CHD related genes. Results (1) Conotruncal defects (CTD) were the most common (69.4%, 43/62) seen CHD in this group. (2) Copy number variations (CNVs >100 kb) were detected in 30 fetuses and CNVs (>1 Mb) were detected in 11 fetuses out of the 30 fetuses (including seven fetuses with determined pathogenic CNVs, six of whom were involved with CTD). (3) Known or suspected pathogenic genes were detected in five fetuses, four of them had ventricular outflow tract obstruction. Conclusions CTD is most common in fetal CHD; most of the fetuses with pathogenic CNVs are complicated with CTD; and most of the fetuses with likely pathogenic genetic mutation are involved with ventricular outflow tract obstruction. Key words: Heart defects, congenital; Genome, human; Chromosome deletion; Chromosome duplication; Polymorphism, single nucleotide; Sequence analysis, DNA