Department of Pathophysiology, Basic Medicine College of Inner Mongolia Medical University, Hohhot, China.
Rehabilitation Department, Ordos Central Hospital, Ordos, China.
Medicine (Baltimore). 2024 Feb 2;103(5):e36977. doi: 10.1097/MD.0000000000036977.
Congenital heart disease (CHD) is the most common birth defect and an important cause of noninfectious deaths in infants and children. It has high prevalence globally, placing an enormous burden on society and families. Studies of individuals with hereditary or sporadic CHD have provided strong evidence for its genetic basis. The aim of this study was to identify causative gene variants in a Chinese family with congenital heart disease.
Three generations of a CHD family were recruited. Proband III.9 was diagnosed with congenital heart disease at age 11 months, and the echocardiogram showed arterial ductus arteriosus, with a left-to-right shunt at the level of the arteries. Precedent III.10 was a twin of Proband III.9 who was diagnosed with congenital heart disease at age 11 months, in whom the echocardiogram revealed an arterial ductus arteriosus, an unenclosed patent ductus arteriosus, and a left to right shunt at the level of the arteries (second figure). III.8 was diagnosed with congenital heart disease at age 15, but echocardiography in this study showed no abnormalities. No cardiac abnormalities were detected in any of his parents, grandparents, or maternal grandparents. We performed whole-exome sequencing on CHD sufferers and their unexpressing family members to investigate the genetic causes of CHD in this family line. Exome sequencing identified 4 mutation sites in this family line. The variant c.3245A>G (p.His1082Arg) of the AMER1 gene was consistent with concomitant X-chromosome recessive inheritance, the variant c.238G>C (p.Val80Leu) of the KCNE1 gene was consistent with autosomal accessory inheritance, and the other 2 variants did not conform to the law of the mode of inheritance of the disease.
The first identified variant, c.3245A>G (p.His1082Arg) of the AMER1 gene, with X-chromosome recessive inheritance, and the variant c.238G>C (p.Val80Leu) of the KCNE1 gene, which has been reported as autosomal dominant, may be the causative agent of CHD in this family line. These findings broaden the genetic scope of congenital heart disease and could help in the development of targeted drugs for the treatment of congenital heart disease.
先天性心脏病（CHD）是最常见的出生缺陷，也是婴儿和儿童非传染性死亡的重要原因。它在全球的发病率很高，给社会和家庭带来了巨大的负担。对遗传性或散发性 CHD 个体的研究为其遗传基础提供了强有力的证据。本研究旨在鉴定一个先天性心脏病家系中的致病基因突变。
该研究纳入了一个 CHD 家系的三代人。先证者 III.9 在 11 个月大时被诊断为先天性心脏病，超声心动图显示动脉导管未闭，存在动脉水平的左向右分流。先例 III.10 是先证者 III.9 的双胞胎，在 11 个月大时被诊断为先天性心脏病，超声心动图显示动脉导管未闭、未闭的动脉导管未闭和动脉水平的左向右分流（第二张图）。III.8 在 15 岁时被诊断为先天性心脏病，但本研究中的超声心动图未显示异常。他的父母、祖父母或外祖父母均未发现心脏异常。我们对 CHD 患者及其无表达的家庭成员进行了全外显子组测序，以研究该家族中 CHD 的遗传原因。外显子组测序在该家族中发现了 4 个突变位点。AMER1 基因的 c.3245A>G(p.His1082Arg) 变异与伴 X 染色体隐性遗传一致，KCNE1 基因的 c.238G>C(p.Val80Leu) 变异与常染色体伴性遗传一致，其他 2 个变异不符合疾病遗传模式的规律。
首先鉴定的 AMER1 基因的 c.3245A>G(p.His1082Arg) 变异与 X 染色体隐性遗传，以及 KCNE1 基因的 c.238G>C(p.Val80Leu) 变异，该变异已被报道为常染色体显性遗传，可能是该家系 CHD 的致病因素。这些发现拓宽了先天性心脏病的遗传范围，并有助于开发针对先天性心脏病的靶向药物。
