Identifying The Rare Variations In A Chinese Sporadic Congenital Heart Disease Cohort

Congenital heart disease(CHD) is a complex disease that the structures of the heart or great vessels are abnormal when the fetus was born. In China, the incidence of CHD is now close to 1%, which makes thousands of neonates born with heart defects. To identify the risk factors of sporadic CHD, kinds of powerful tools were used to detect the rare variations in a sporadic CHD cohort. We performed 4 pooled exome sequencing on 66 CHD patients according to the clinical subtypes of CHD. After data analysis and validation, we genotyped the SNV(single nucleotide variation) sites in 800 normal samples to rule out the common variations. Here we present a rare variations spectrum which contains 387 non-synonymous mutations in a sporadic CHD cohort, including 351 missense mutations, 14 splicing site mutations and 22 nonsense mutations. On that basis, several candidate genes were selected to sequence the coding regions in an expanded CHD population(n=217). Finally we identified 19 rare variations in PKD1L1(P=9.434e-14), 11 rare variations in DLC1(P=1.208e-8) and 6 rare variations in FAM71A(P=8.932e-5). Compared with the rare variations frequency of PKD1L1 in 400 normal samples, our data demonstrate that the rare variations of PKD1L1 are significantly recruited in the CHD cohort(P=2.736e-6). In addition, the damage evaluation of these rare variants using SIFT scores indicates that they are more inclined to disrupt the protein(P<0.001). In the other hand, we used Affymetrix 500 K array to scan the genomes of 58 CHD patients and a few copy number variations were also identified. For the first time, our study identifies a series of rare variations which were only found in the Chinese sporadic CHD cohort, and more importantly, we provide strong evidence that the rare variations of PKD1L1 are associated with the sporadic congenital heart disease. All of these efforts are essential for the continued studies to explore the genetic factors of CHD.