Identification of SOX18 as a New Gene Predisposing to Congenital Heart Disease

Abstract

Congenital heart disease (CHD) is the most frequent kind of birth deformity in human beings and the leading cause of neonatal mortality worldwide. Although genetic etiologies encompassing aneuploidy, copy number variations, and mutations in over 100 genes have been uncovered to be involved in the pathogenesis of CHD, the genetic components predisposing to CHD in most cases remain unclear. We recruited a family with CHD from the Chinese Han population in the present investigation. Through whole-exome sequencing analysis of selected family members, a new SOX18 variation, namely NM_018419.3:c.349A>T; p.(Lys117*), was identified and confirmed to co-segregate with the CHD phenotype in the entire family by Sanger sequencing analysis. The heterozygous variant was absent from the 384 healthy volunteers enlisted as control individuals. Functional exploration via luciferase reporter analysis in cultivated HeLa cells revealed that Lys117*-mutant SOX18 lost transactivation on its target genes NR2F2 and GATA4, two genes responsible for CHD. Moreover, the genetic variation terminated the synergistic activation between SOX18 and NKX2.5, another gene accountable for CHD. The findings strongly indicate SOX18 as a novel gene contributing to CHD, which helps address challenges in the clinical genetic diagnosis and prenatal prophylaxis of CHD.

Increased gestational palmitic acid predisposes offspring to congenital heart disease

“…Congenital heart disease (CHD), which refers to a wide spectrum of structural malformations occurring in the heart, valves, and endothoracic great blood vessels during embryonic cardiogenesis, represents the most prevalent kind of human birth defect, with an estimated prevalence of 1% in newborns and up to 10% in stillbirths worldwide. 2 , 3 Although tiny CHD can resolve spontaneously, severe CHD may give rise to worse health-related quality of life, reduced exercise performance, pulmonary arterial hypertension, restrictive lung dysfunction, kidney damage, impaired hepatic function, delayed neurodevelopment, brain injury, thromboembolism, infective endocarditis, congestive heart failure, cardiac arrhythmias, and sudden cardiac death. 2 , 3 Striking advance has been achieved recently in pediatric cardiovascular surgical and interventional procedures, as well as perioperative intensive care, which allows approximately 95% of children afflicted with CHD to survive into adulthood, consequently yielding an ever-increasing population of adult affected individuals reaching reproductive age, and presently, adults already outnumber children who live with CHD.…”

“… 2 , 3 Although tiny CHD can resolve spontaneously, severe CHD may give rise to worse health-related quality of life, reduced exercise performance, pulmonary arterial hypertension, restrictive lung dysfunction, kidney damage, impaired hepatic function, delayed neurodevelopment, brain injury, thromboembolism, infective endocarditis, congestive heart failure, cardiac arrhythmias, and sudden cardiac death. 2 , 3 Striking advance has been achieved recently in pediatric cardiovascular surgical and interventional procedures, as well as perioperative intensive care, which allows approximately 95% of children afflicted with CHD to survive into adulthood, consequently yielding an ever-increasing population of adult affected individuals reaching reproductive age, and presently, adults already outnumber children who live with CHD. 3 Surprisingly, the elongated average lifespan of CHD survivors is associated with a significantly increased long-term risk for morbidity and mortality, including cancer, pulmonary hypertension, renal dysfunction, thrombosis, aortopathy, heart failure, dysrhythmias, and cardiac demise.…”

“… 2 , 3 Striking advance has been achieved recently in pediatric cardiovascular surgical and interventional procedures, as well as perioperative intensive care, which allows approximately 95% of children afflicted with CHD to survive into adulthood, consequently yielding an ever-increasing population of adult affected individuals reaching reproductive age, and presently, adults already outnumber children who live with CHD. 3 Surprisingly, the elongated average lifespan of CHD survivors is associated with a significantly increased long-term risk for morbidity and mortality, including cancer, pulmonary hypertension, renal dysfunction, thrombosis, aortopathy, heart failure, dysrhythmias, and cardiac demise. 3 , 4 Obviously, CHD has imposed a tremendous socioeconomic burden on human beings, underscoring the urgent need to unravel the molecular basis underpinning CHD.…”

“… 3 Surprisingly, the elongated average lifespan of CHD survivors is associated with a significantly increased long-term risk for morbidity and mortality, including cancer, pulmonary hypertension, renal dysfunction, thrombosis, aortopathy, heart failure, dysrhythmias, and cardiac demise. 3 , 4 Obviously, CHD has imposed a tremendous socioeconomic burden on human beings, underscoring the urgent need to unravel the molecular basis underpinning CHD.…”

Discovery of GJC1 (Cx45) as a New Gene Underlying Congenital Heart Disease and Arrhythmias

“…Genetic defects responsible for CHD include aneuploidy (presence of an additional chromosome, absence of a chromosome, or deletion/duplication of one arm of a chromosome), copy number variation (deletion or duplication of a segment of a chromosome), and genetic mutations [ 44 , 45 , 46 ]. To date, pathogenic mutations in over 100 genes have been involved in the occurrence of CHD, of which most encode cardiac transcription factors, cell adhesion molecules, signaling pathway proteins, and cardiac structural proteins essential for cardiovascular morphogenesis [ 44 , 45 , 46 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ]. However, CHD is of pronounced genetic heterogeneity, and the genetic determinants causative for CHD in a significant proportion of cases remain to be identified.…”