Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, 139 Renmin Central Road, Changsha, 410011, Hunan, People's Republic of China.
Central South University Center for Clinical Gene Diagnosis and Treatment, the Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China.
BMC Cardiovasc Disord. 2021 Jan 6;21(1):12. doi: 10.1186/s12872-020-01822-5.
Although most cases of atrial septal defect (ASD) are sporadic, familial cases have been reported, which may be caused by mutation of transcription factor GATA binding protein 4 (GATA4). Herein we combined whole-exome sequencing and bioinformatics strategies to identify a novel mutation in GATA4 accounting for the etiology in a Chinese family with ASD.
We identified kindred spanning 3 generations in which 3 of 12 (25.0%) individuals had ASD. Punctilious records for the subjects included complete physical examination, transthoracic echocardiography, electrocardiograph and surgical confirming. Whole-exome capture and high-throughput sequencing were performed on the proband III.1. Sanger sequencing was used to validate the candidate variants, and segregation analyses were performed in the family members.
Direct sequencing of GATA4 from the genomic DNA of family members identified a T-to-C transition at nucleotide 929 in exon 5 that predicted a methionine to threonine substitution at codon 310 (M310T) in the nuclear localization signal (NLS) region. Two affected members (II.2 and III.3) and the proband (III.1) who was recognized as a carrier exhibited this mutation, whereas the other unaffected family members or control individuals did not. More importantly, the mutation GATA4 (c.T929C: p.M310T) has not been reported previously in either familial or sporadic cases of congenital heart defects (CHD).
We identified for the first time a novel M310T mutation in the GATA4 gene that is located in the NLS region and leads to family ASD with arrhythmias. However, the mechanism by which this pathogenic mutation contributes to the development of heart defect and tachyarrhythmias remains to be ascertained.
虽然大多数房间隔缺损（ASD）是散发性的，但也有家族性病例的报道，这可能是由转录因子 GATA 结合蛋白 4（GATA4）的突变引起的。在此，我们结合全外显子组测序和生物信息学策略，鉴定了一个导致中国 ASD 家系发病的 GATA4 新突变。
我们鉴定了一个跨越 3 代的家系，其中 12 名（25.0%）个体中有 3 名患有 ASD。对受试者进行了详细的记录，包括完整的体格检查、经胸超声心动图、心电图和手术确认。对先证者 III.1 进行全外显子捕获和高通量测序。对候选变体进行 Sanger 测序验证，并在家族成员中进行分离分析。
对家系成员的 GATA4 基因组 DNA 进行直接测序，发现外显子 5 中第 929 位核苷酸发生 T 到 C 的转换，导致核定位信号（NLS）区域的第 310 位密码子（M310T）由蛋氨酸突变为苏氨酸。2 名受影响的成员（II.2 和 III.3）和被认定为携带者的先证者（III.1）均表现出该突变，而其他未受影响的家族成员或对照个体则没有。更重要的是，该突变 GATA4（c.T929C：p.M310T）以前在家族性或散发性先天性心脏病（CHD）病例中均未报道过。
我们首次在 GATA4 基因中发现位于 NLS 区域的新型 M310T 突变，该突变导致家族性 ASD 伴心律失常。然而，这种致病突变导致心脏缺陷和心动过速的机制仍有待确定。
