Zhang Haixia, Chen Jing, Wang He, Xiang Qinqin, Liu Shanling
Department of Medical Genetics/Prenatal Diagnostic Center, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, Sichuan, China.
Front Genet. 2025 Jul 9;16:1498144. doi: 10.3389/fgene.2025.1498144. eCollection 2025.
NK2 HOMEOBOX 5(OMIM: 600584, ), a pivotal cardiac regulatory transcription factor, represents the initial identified genetic etiology underlying congenital heart diseases (CHDs). As a member of the NK homeobox gene family, functions as an essential DNA-binding transcriptional activator. It demonstrates robust expression levels in both primary and secondary heart fields' cardiac progenitor cells, playing an indispensable role in cardiovascular development. Here we reported a nonsense variant in a Chinese family with nonsyndromic congenital heart disease.
Trio-whole-exome sequencing (Trio-WES) was performed on the proband and parents, followed by Sanger sequencing for verification and linkage analysis using available DNA samples from this family and additional family members. A nonsense variant (NM_004387.4: c.342C>A, p.(Cys114*)) was identified within the gene through Trio-WES analysis and classified as likely pathogenic according to the criteria of the ACMG. Sanger sequencing revealed the presence of this nonsense variant in all affected family members (II1, II3, III1, and III5) within the gene, while unaffected family members (II2, II7, and II8) did not exhibit this variant.
The present study identified a heterozygous nonsense variant of the gene in a family with nonsyndromic congenital heart disease, suggesting that this variant may be the underlying cause of the disease within this particular family. Our findings suggests that it can cause diverse phenotypes and varying severity of cardiac abnormalities even within the family. Additionally, an early and definitive genetic diagnosis can provide precise information for subsequent treatment and fertility counseling.
NK2同源盒蛋白5（OMIM: 600584）是一种关键的心脏调节转录因子，是先天性心脏病（CHD）最初确定的遗传病因。作为NK同源盒基因家族的成员，它作为一种必需的DNA结合转录激活因子发挥作用。它在原发性和继发性心脏区域的心脏祖细胞中均表现出较高的表达水平，在心血管发育中发挥着不可或缺的作用。在此，我们报告了一个非综合征性先天性心脏病中国家系中的一个无义变异。
对先证者及其父母进行了三联全外显子测序（Trio-WES），随后进行Sanger测序以验证，并使用该家系及其他家庭成员的可用DNA样本进行连锁分析。通过Trio-WES分析在该基因内鉴定出一个无义变异（NM_004387.4: c.342C>A, p.(Cys114*))，并根据ACMG标准分类为可能致病。Sanger测序显示该基因内所有受影响的家庭成员（II1、II3、III1和III5）均存在此无义变异，而未受影响的家庭成员（II2、II7和II8）未表现出该变异。
本研究在一个非综合征性先天性心脏病家系中鉴定出该基因的一个杂合无义变异，表明该变异可能是该特定家系中疾病的潜在病因。我们的研究结果表明，即使在家族内部，它也可导致不同的表型和心脏异常的不同严重程度。此外，早期明确的基因诊断可为后续治疗和生育咨询提供精确信息。
