%0 Journal Article
%T Analysis of the CHD7 gene mutations in patients of congenital heart disease with extracardiac malformations.
%A Huang X
%A Gao H
%A Chen W
%A Feng Z
%A Tan C
%A Zhuang Q
%A Wang J
%A Gao Y
%A Min S
%A Yao Q
%A Sun J
%A Yan W
%A Ma X
%A Wu F
%A Sheng W
%A Huang G
%J Transl Pediatr
%V 12
%N 6
%D 2023 Jun 30
%M 37427070
%F 4.047
%R 10.21037/tp-22-634
%X <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.