Targeted Next-Generation Sequencing of 406 Genes Identified Genetic Defects Underlying Congenital Heart Disease in Down Syndrome Patients

Abstract

Down syndrome (DS) is the most common autosomal chromosome anomaly. DS is frequently associated with congenital heart disease (CHD). Patients with DS have 40-60% chance of having CHD. It means that CHD in DS is not only due to trisomy 21 and there are some other genetic factors underlying CHD in DS children. In this study, a total of 240 DNA samples from patients were analyzed including 100 patients with CHD only, 110 patients having CHD along with DS and 30 patients with isolated DS. A cardiovascular gene panel consisting of probes for 406 genes was used to screen DNA samples of all 240 patients for mutation identification. All variants were annotated and common variants were obtained. Briefly, 28 common variants (variants common in two or more than two individuals) were obtained in a group of samples containing DNA from DS patients having CHD as well, 63 variants were found to be unique to DS group of samples and 73 variants have been identified in patients with CHD only. In order to identify genomic variations determining the risk for CHD in DS, only those variants present in DS-CHD group and absent in isolated CHD and/or isolated DS group were considered for further analysis. Variants specific to DS-CHD group were further evaluated based on expression and function data and pathogenicity of the variant of interest. We have implicated mutations in GATA3, KCNH2, ENG, FLNA, and GUSB genes as an underlying risk factor for CHD in DS patients.

Maternal risk factors for congenital heart defects in infants with Down syndrome from Western Mexico

“…At present, ethnic differences in frequency of the individual subtypes of CHDs between infants with DS have not been explained only by the karyotype or by a single gene or group of genes on chromosome 21 (Frid et al, ). Consequently, there have been proposed further genetic or gene–environmental interactions involving SNPs and CNVs located in chromosome 21 that can modify particularly the risk for AVSDs (Sailani et al, ) or mutations in autosomal genes not located on chromosome 21, such as GATA3 , KCNH2 , ENG , FLNA , GUSB , SH3BGR , and CRELD1 (Alharbi et al, ; Kerstann et al, ; Maslen et al, ), methylenetetrahydrofolate reductase (MTHFR) variants (Brandalize, Bandinelli, dos Santos, Roisenberg, & Schüler‐Faccini, ), or even, dermatoglyphic differences (Durham & Koehler, ). Besides, other maternal risk factors have also been implicated including consanguinity (Mokhtar & Abdel‐Fattah, ; El‐Gilany, Yahia, & Wahba, (2017), obesity (Bergström et al, ), diabetes (Mokhtar & Abdel‐Fattah, ), lack of folic acid (FA) supplementation before pregnancy (Bean et al, ; El‐Gilany, Yahia, & Wahba, ), first‐trimester exposure to oral contraceptive pills (Mokhtar & Abdel‐Fattah, ), and tobacco smoking (Torfs & Christianson, 1999; El‐Gilany, Yahia, & Wahba, ; Bergström et al, ).…”

Identifying genetic factors that contribute to the increased risk of congenital heart defects in infants with Down syndrome

“…In our analyses, NOTCH4 and CEP290, whose roles in heart development and the ciliome have been previously described 36,37 , were found to have nominally significant associations with DS + AVSD in both WES and WGS datasets. CEP290 was also recently identified as potentially associated with non-syndromic CHD (including any type of heart defect) by a targeted sequencing study of 406 candidate genes involved in heart development 41 .…”

Congenital heart defects associated with aneuploidy syndromes: New insights into familiar associations

“…Analysis of patients with partial trisomy 21 identified a candidate region for CHDs (Pelleri et al, ). Next‐generation sequencing implicated candidate genes for CHD in patients with Down syndrome (Alharbi et al, ). These and other studies suggest that the prevalence of CHDs, and AVSD, in particular, in Down syndrome is likely multifactorial and related to a complex interplay between genes on chromosome 21 with variants elsewhere in the genome.…”