{Reference Type}: Journal Article
{Title}: Analysis of the CHD7 gene mutations in patients of congenital heart disease with extracardiac malformations.
{Author}: Huang X;Gao H;Chen W;Feng Z;Tan C;Zhuang Q;Wang J;Gao Y;Min S;Yao Q;Sun J;Yan W;Ma X;Wu F;Sheng W;Huang G;
{Journal}: Transl Pediatr
{Volume}: 12
{Issue}: 6
{Year}: 2023 Jun 30
{Factor}: 4.047
{DOI}: 10.21037/tp-22-634
{Abstract}: <B>UNASSIGNED: </B>Congenital heart disease (CHD) is a common birth defect, and is frequently accompanied with extracardiac malformations (ECM). Uncovering the genetic etiology of CHD may have a meaningful impact on disease management. De novo variants have been proven to be associated with CHD.<BR><B>UNASSIGNED: </B>Whole exome sequencing was performed for 4 unrelated CHD families with extracardiac malformations, candidate genes were screened by using stringent bioinformatics analysis, and the obtained variants were confirmed by Sanger sequencing. RT-PCR and Sanger sequencing were used to investigate the influence of a splice variant on pre-mRNA splicing. Further targeted sequencing was conducted to investigate the association of CHD7 variants with sporadic CHD.<BR><B>UNASSIGNED: </B>Four novel heterozygous loss-of-function CHD7 mutations were found by using stringent bioinformatics analysis: the frameshift mutation c.1951_1952delAAinsT (p.L651X) in family #1, the nonsense mutations c.2913C>G (p.Y971X) in family #2 and c.3106C>T (pA1036X) in family #3, and the splicing mutation c.4353+4_4353+12delinsGCCCA in family #4. Sanger sequencing confirmed that these were all de novo mutations and were absent in the healthy parents and siblings of the probands. Further studies revealed that the splice mutation c.4353+4_4353+12delinsGCCCA influenced CHD7 mRNA splicing in vivo. Targeted sequencing found 23 rare mutations in 1,155 sporadic CHD patients.<BR><B>UNASSIGNED: </B>The findings here confirm that de novo loss-of-function variants of the CHD7 gene are the genetic cause of familial CHD with extracardiac malformations and the spectrum of pathogenic CHD7 variants in sporadic CHD is expanded.