The M310T mutation in the GATA4 gene is a novel pathogenic target of the familial atrial septal defect

Abstract

Background 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. Methods 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. Results 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). Conclusions 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.

Copy number variation characterization and possible candidate genes in miscarriage and stillbirth by next‐generation sequencing analysis

“… 57 Variants in the GATA binding protein 4 ( GATA4 ) gene cause congenital heart disease. 58 Variants in the serine peptidase inhibitor Kazal type 5 ( SPINK5 ) gene are involved in the molecular etiology of congenital ichthyosis. 59 Microdeletions in neuroligin 4 X‐linked ( NLGN4X ) gene can affect neurodevelopment.…”

A Pilot Study of Multiplex Ligation-Dependent Probe Amplification Evaluation of Copy Number Variations in Romanian Children with Congenital Heart Defects

“…It plays an important role in the development of the atrioventricular region, including valvular development, due to its high expression at the level of endocardial cushions [44,45]. Genetic alterations of GATA4, especially single nucleotide polymorphisms (SNPs), have been linked to CHDs in the human population, associations being made with atrial septal defects (ASDs), ventricular septal defects, atrioventricular septal defects, tetralogy of Fallot, pulmonary stenosis, and pulmonary atresia [46][47][48][49][50]. Studies have also reported CNVs involving this gene.…”

Identification and functional analysis of genetic variants of ISL1 gene promoter in human atrial septal defects

“…8,11 Atrial septal defect (ASD) is one of the most common types of CHD 12 , accounting for 10% of CHD. 13 ASD might not be diagnosed until it appears in adulthood and therefore the incidence of ASD is usually higher than estimated. 14 Although studies have found that cardiac core transcription factor genes, encompassing NKX2-5, GATA4 and TBX5, are involved in ASD, 15 to date the genetic causes of ASD remain largely unknown.…”

“…The majority of these genes code for transcription factors that modulate specific events in cardiac development 8,11 . Atrial septal defect (ASD) is one of the most common types of CHD 12 , accounting for 10% of CHD 13 . ASD might not be diagnosed until it appears in adulthood and therefore the incidence of ASD is usually higher than estimated 14 .…”