Familial Atrial Septal Defect Research Articles

A Novel Splicing Mutation c.335–1 G > A in the Cardiac Transcription Factor NKX2-5 Leads to Familial Atrial Septal Defect Through miR-19 and PYK2

Mutations of NKX2-5 largely contribute to congenital heart diseases (CHDs), especially atrial septal defect (ASD). We identified a novel heterozygous splicing mutation c.335-1G > A in NKX2-5 gene in an ASD family via whole exome sequencing (WES) and linkage analysis. Utilizing the human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs) as a disease model, we showed that haploinsufficiency of NKX2-5 contributed to aberrant orchestration of apoptosis and proliferation in ASD patient-derived hiPSC-CMs. RNA-seq profiling and dual-luciferase reporter assay revealed that NKX2-5 acts upstream of PYK2 via miR-19a and miR-19b (miR-19a/b) to regulate cardiomyocyte apoptosis. Meanwhile, miR-19a/b are also downstream mediators of NKX2-5 during cardiomyocyte proliferation. The novel splicing mutation c.335-1G > A in NKX2-5 and its potential pathogenic roles in ASD were demonstrated. Our work provides clues not only for deep understanding of NKX2-5 in cardia development, but also for better knowledge in the molecular mechanisms of CHDs.

Novel Functional FOXC1 Variants in Familial and Sporadic Atrial Septal Defect

ObjectiveAtrial septal defect (ASD) is one of the most common forms of congenital heart disease. Genetic defects play important roles in the pathogenesis of ASD but are complex and unclear. This study tries to discover the genetic pathogenesis in familial and sporadic ASD patients.MethodsIn Stage I, in a family with 30 members whole exome sequencing was performed in 4 ASD patients and the identified genetic variants were screened in the rest of the family members. In Stage II, 335 unrelated sporadic and isolated ASD patients were enrolled to test whether the genetic variants were involved in these patients. In Stage III, biological functions of the variants were elucidated at the cellular level and the CRISPR/Cas9 was used to construct variant‐specific mutant mice in order to observe the abnormality of the heart structure.ResultsA novel heterozygous missense variant, FOXC1 c.518G>A (p.R173H) was identified in the ASD family by whole exome sequencing. Subsequently, other 4 heterozygous variants in FOXC1, including 2 novel missense variants: c.556‐558delAAG (p.K186del) and c.559G>A (p.D187N) were identified in unrelated 335 sporadic ASD patients. In dual‐luciferase reporter assay, the transcriptional activity of R173H decreased to almost 30% of the wild‐type. In the Foxc1 R173H site‐specific mutant mice, the atrial septum became very thin in tissue slices of the heart that was similar to the echocardiographic finding in the above family members.ConclusionVariants in FOXC1 likely cause cardiac anomaly, particularly ASD. These findings provide a new insight into genetic mechanisms and counseling of familial and sporadic ASD.

NKX2-5 variants screening in patients with atrial septal defect in Indonesia

BackgroundNKX2-5 variant in atrial septal defect patients has been reported. However, it is not yet been described in the Southeast Asian population. Here, we screened the NKX2-5 variants in patients with atrial septal defect (ASD) in the Indonesian population.MethodWe recruited 97 patients with ASD for genetic screening of the NKX2-5 variant using Sanger sequencing.ResultsWe identified three variants of NKX2-5: NM_004387.4:c.63A>G at exon 1, NM_004387.4:c.413G>A, and NM_004387.4:c.561G>C at exon 2. The first variant is commonly found (85.6%) and benign. The last two variants are heterozygous at the same locus. These variants are rare (3.1%) and novel. Interestingly, these variants were discovered in familial atrial septal defects with a spectrum of arrhythmia and severe pulmonary hypertension.ConclusionOur study is the first report of the NKX2-5 variant in ASD patients in the Southeast Asian population, including a novel heterozygous variant: NM_004387.4:c.413G>A and NM_004387.4:c.561G>C. These variants might contribute to familial ASD risk with arrhythmia and severe pulmonary hypertension. Functional studies are necessary to prove our findings.

Comparison of Outcome in Patients With Familial Versus Spontaneous Atrial Septal Defect

Patients with atrial septal defects (ASDs) have increased mortality and morbidity. This can only partly be explained by hemodynamic changes caused by the ASD, suggesting additional underlying causes. Patients with an ASD have an increased burden of pathogenic gene variants in ASD-related genes, indicating genetics as an important factor in etiology. Inheritance of genetic variants with high impact can cause ASD in relatives (familial ASD). This study aimed to investigate whether lifelong outcomes were different in patients with familial ASD compared with patients with sporadic ASD. We used health registries and a nationwide cohort of 2,151 patients with ASD to compare the incidences of atrial fibrillation or flutter (together abbreviated as AF), heart failure, and mortality between patients with familial and sporadic ASD using Cox proportional hazard ratio and Fine and Gray analysis. Patients with familial ASD experienced AF and heart failure earlier in life than patients with sporadic ASD, with hazard ratios of 1.6 and 1.7, respectively. Subdistribution hazard ratios showed an increased risk of AF and heart failure in patients with familial ASD compared with patients with sporadic ASDs (2.3 and 3.1, respectively). Our results suggest that genetic variants with high impact may influence the outcomes of patients with ASD. In conclusion, patients with familial ASD have an increased risk and an earlier onset of AF and heart failure compared with patients with sporadic ASD, hence clinical awareness of arrhythmias and heart failure in patients with familial ASD may lead to timely treatment.

A novel NKX2–5 double variant corresponds with familial atrial septal defect with arrhythmia in Indonesia

Abstract Background The transcription factor NKX2–5 is essential for heart development during embryonic stages. The genetic variant of NKX2–5 is founded in many congenital heart diseases, especially atrial septal defect (ASD). Most of NKX2–5 variants in Asia based on Chinese population are single nucleotide polymorphisms. Whether the same variant of NKX2–5 is also involved in Southeast Asia population is still unknown. Therefore, we investigate the NKX2–5 variant in atrial septal defect population in Indonesia. Purpose To investigate the genetic variation of NKX2–5 in ASD in Indonesian population. Methods We screened 97 patients with ASD (including 23 familial patients) for sequence variant in NKX2–5. DNA samples were extracted from venous blood samples. The whole two coding exons of the NKX2–5 gene from DNA samples were amplified by multiplex PCR and directly sequenced. Variations were detected by comparison with the standard reference genome. The distribution of genotype frequency in atrial septal disease familial and non-familial were analyzed. Results We identified a novel heterozygous DNA sequence double variant (c413 G>A, rs1366528649 and c561 G>C, rs767559311) in exon 2 of NKX2–5 gene was identified only in 3 familial ASD patients. These patients are related to first-degree relatives. Patients with these double variants have septal defects and arrhythmias in young-to middle-aged adults (sinus node dysfunction dan atrial tachycardia). Moreover, one reported single nucleotide polymorphisms (SNPs) (c63 A>G, rs2277923) was detected in 83 patients (85.6%), as 20 patients (87%) were present among the familial group, and 63 patients (85.1%) were found from the non-familial group. The distribution of rs2277923 variation among the familial and non-familial groups was not different. Variation of rs2277923 has 2 genotypes: homozygous AG presented in 42 patients (43.3%) and heterozygous AG shown in 41 patients (42.3%). The distribution of both genotypes is also similar between familial and non-familial groups. Conclusions We discovered that the novel NKX2–5 double variants (rs1366528649 and rs767559311) might contribute to familial ASD risk, although the rs2277923 is the most commonly found variant in ASD patients in Indonesia. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dana Masyarakat Faculty of Medicine, Public Health and Nursing UGM fiscal years 2020

Abstract P305: Patient-specific Ipsc-derived Cardiomyocytes Reveal Abnormal Regulation Of Fgf16 In A Familial Atrial Septal Defect

Aims: Congenital heart disease (CHD) frequently occurs in newborns due to abnormal formation of the heart or major blood vessels. Mutations in the GATA4 gene, which encodes GATA binding protein 4, are responsible for atrial septal defect (ASD), a common CHD. This study aims to gain insights into the molecular mechanisms of CHD using human induced pluripotent stem cells (iPSCs) from a family cohort with ASD. Methods and Results: Patient-specific iPSCs possess the same genetic information as the donor and can differentiate into various cell types from all three germ layers in vitro , thus presenting a promising approach for disease modeling and molecular mechanism research. Here, we generated a patient-specific iPSC line (iPSC-G4 T280M ) from a family cohort carrying a hereditary ASD mutation in GATA4 gene (T280M), as well as a human embryonic stem cell line (ESC-G4 T280M ) carrying the isogenic T280M mutation using the CRISPR/Cas9 genome editing method. The GATA4-mutant iPSCs and ESCs were then differentiated into cardiomyocytes (CMs) to model GATA4 mutation-associated ASD. We observed an obvious defect in cell proliferation in cardiomyocytes derived from both GATA4 T280M -mutant iPSCs (iPSC-G4 T280M -CMs) and ESCs (ESC-G4 T280M -CMs), while the impaired proliferation ability of iPSC-G4 T280M -CMs could be restored by gene correction. Integrated analysis of RNA-Seq and ChIP-Seq data indicated that FGF16 is a direct target of wild-type GATA4. However, the T280M mutation obstructed GATA4 occupancy at the FGF16 promoter region, leading to impaired activation of FGF16 transcription. Overexpression of FGF16 in GATA4-mutant cardiomyocytes rescued the cell proliferation defect. The direct relationship between GATA4 T280M and ASD was demonstrated in a human iPSC model for the first time. Conclusions: In summary, our study revealed the molecular mechanism of the GATA4 T280M mutation in ASD. Understanding the roles of the GATA4-FGF16 axis in iPSC-CMs will shed light on heart development and provide novel insights for the treatment of ASD and other CHD disorders.

Novel insertion mutation (Arg1822_Glu1823dup) in MYH6 coiled-coil domain causing familial atrial septal defect

ObjectiveAtrial septal defect, secundum (ASD Ⅱ, OMIM: 603642) is the second common congenital heart defect (CHD) in China. However, the genetic etiology of familial ASD II remains elusive. Methods and resultsUsing whole-exome sequencing (WES) and Sanger sequencing, we identified a novel myosin heavy chain 6 (MYH6) gene insertion variation, NM_002471.3: c.5465_5470dup (Arg1822_Glu1823dup), in a large Chinese Han family with ASD II. The variant Arg1822_Glu1823dup co-segregated with the disease in this family with autosomal dominant inheritance. The insertion variant located in the coiled-coil domain of the MYH6 protein, which is highly conserved across homologous myosin proteins and species. In transfected myoblast C2C12 cell lines, the MYH6 Arg1822_Glu1823dup variant significantly impaired myofibril formation and increased apoptosis but did not significantly reduce cell viability. Furthermore, molecular simulations revealed that the Arg1822_Glu1823dup variant impaired the myosin α-helix, increasing the stability of the coiled-coil myosin dimer, suggesting that this variant has an effect on the coiled-coil domain self-aggregation. These findings indicate that Arg1822_Glu1823dup variant plays a crucial role in the pathogenesis of ASD II. ConclusionOur findings expand the spectrum of MYH6 variations associated with familial ASD II and may provide a molecular basis in genetic counseling and prenatal diagnosis for this Chinses family.

Patient-specific iPSC-derived cardiomyocytes reveal abnormal regulation of FGF16 in a familial atrial septal defect.

Congenital heart disease (CHD) frequently occurs in newborns due to abnormal formation of the heart or major blood vessels. Mutations in the GATA4 gene, which encodes GATA binding protein 4, are responsible for atrial septal defect (ASD), a common CHD. This study aims to gain insights into the molecular mechanisms of CHD using human-induced pluripotent stem cells (iPSCs) from a family cohort with ASD. Patient-specific iPSCs possess the same genetic information as the donor and can differentiate into various cell types from all three germ layers in vitro, thus presenting a promising approach for disease modelling and molecular mechanism research. Here, we generated a patient-specific iPSC line (iPSC-G4T280M) from a family cohort carrying a hereditary ASD mutation in GATA4 gene (T280M), as well as a human embryonic stem cell line (ESC-G4T280M) carrying the isogenic T280M mutation using the CRISPR/Cas9 genome editing method. The GATA4-mutant iPSCs and ESCs were then differentiated into cardiomyocytes (CMs) to model GATA4 mutation-associated ASD. We observed an obvious defect in cell proliferation in cardiomyocytes derived from both GATA4T280M-mutant iPSCs (iPSC-G4T280M-CMs) and ESCs (ESC-G4T280M-CMs), while the impaired proliferation ability of iPSC-G4T280M-CMs could be restored by gene correction. Integrated analysis of RNA-Seq and ChIP-Seq data indicated that FGF16 is a direct target of wild-type GATA4. However, the T280M mutation obstructed GATA4 occupancy at the FGF16 promoter region, leading to impaired activation of FGF16 transcription. Overexpression of FGF16 in GATA4-mutant cardiomyocytes rescued the cell proliferation defect. The direct relationship between GATA4T280M and ASD was demonstrated in a human iPSC model for the first time. In summary, our study revealed the molecular mechanism of the GATA4T280M mutation in ASD. Understanding the roles of the GATA4-FGF16 axis in iPSC-CMs will shed light on heart development and provide novel insights for the treatment of ASD and other CHD disorders.

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

BackgroundAlthough 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.MethodsWe 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.ResultsDirect 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).ConclusionsWe 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.

Cardiac α-Actin (ACTC1) Gene Mutation Causes Atrial-Septal Defects Associated With Late-Onset Dilated Cardiomyopathy.

Familial atrial septal defect (ASD) has previously been attributed primarily to mutations in cardiac transcription factors. Here, we report a large, multi-generational family (78 members) with ASD combined with a late-onset dilated cardiomyopathy and further characterize the consequences of mutant α-actin. We combined a genome-wide linkage analysis with cell biology, microscopy, and molecular biology tools to characterize a novel ACTC1 (cardiac α-actin) mutation identified in association with ASD and late-onset dilated cardiomyopathy in a large, multi-generational family. Using a genome-wide linkage analysis, the ASD disease locus was mapped to chromosome 15q14 harboring the ACTC1 gene. In 15 affected family members, a heterozygous, nonsynonymous, and fully penetrant mutation (p. Gly247Asp) was identified in exon 5 of ACTC1 that was absent in all healthy family members (n=63). In silico tools predicted deleterious consequences of this variant that was found absent in control databases. Ultrastructural analysis of myocardial tissue of one of the mutation carriers showed sarcomeric disarray, myofibrillar degeneration, and increased apoptosis, while cardiac proteomics revealed a significant increase in extracellular matrix proteins. Consistently, structural defects and increased apoptosis were also observed in neonatal rat ventricular cardiomyocytes overexpressing the mutant, but not native human ACTC1. Molecular dynamics studies and additional mechanistic analyses in cardiomyocytes confirmed actin polymerization/turnover defects, thereby affecting contractility. A combined phenotype of ASD and late-onset heart failure was caused by a heterozygous, nonsynonymous ACTC1 mutation. Mechanistically, we found a shared molecular mechanism of defective actin signaling and polymerization in both cardiac development and contractile function. Detection of ACTC1 mutations in patients with ASD may thus have further clinical implications with regard to monitoring for (late-onset) dilated cardiomyopathy.

Arrhythmias and conduction disorders associated with atrial septal defects

Atrial septal defects (ASDs) are the most common form of congenital heart disease. There are 4 embryologic types of ASDs, and rhythm considerations vary based on type. ASDs have left-to-right shunt and primarily right-sided volume overload. This leads to electrical remodeling that may predispose patients to atrial tachyarrhythmias and conduction disorders. Risk for arrhythmias is increased with late age of ASD repair, shunt size, other factors such as pulmonary hypertension and comorbid conditions. Arrhythmia incidence is decreased after ASD closure, but remains elevated compared to general population. Medical and procedural therapy for arrhythmias should consider type and timing of ASD repair. Conduction disorders are rare. Sinus node dysfunction may be seen with late age of repair and large shunt size. Sinus venosus ASD exhibits a higher rate of sinus node dysfunction, especially with older surgical techniques. Ostium primum ASD has higher risk of spontaneous or post-operative AV block, though this is rare with current surgical techniques. Risk of AV block with surgical repair or device closure of secundum ASD is rare. Familial ASDs and other forms of congenital heart disease may be seen with mutations in associated myocardial transcription factors NKX2.5, GATA4, TBX6, along with conduction disorders such as AV block.

A family with NKX2.5 gene mutations presenting as familial atrial septal defect and atrioventricular block: A case report

A family with <i>NKX2.5</i> gene mutations presenting as familial atrial septal defect and atrioventricular block: A case report

Highlights From the Circulation Family of Journals

Highlights From the <i>Circulation</i> Family of Journals

Utilization of Whole Exome Sequencing to Identify Causative Mutations in Familial Congenital Heart Disease.

Congenital heart disease (CHD) is the most common type of birth defect with family- and population-based studies supporting a strong genetic cause for CHD. The goal of this study was to determine whether a whole exome sequencing (WES) approach could identify pathogenic-segregating variants in multiplex CHD families. WES was performed on 9 kindreds with familial CHD, 4 with atrial septal defects, 2 with patent ductus arteriosus, 2 with tetralogy of Fallot, and 1 with pulmonary valve dysplasia. Rare variants (<1% minor allele frequency) that segregated with disease were identified by WES, and variants in 69 CHD candidate genes were further analyzed. These selected variants were subjected to in silico analysis to predict pathogenicity and resulted in the discovery of likely pathogenic mutations in 3 of 9 (33%) families. A GATA4 mutation in the transactivation domain, p.G115W, was identified in familial atrial septal defects and demonstrated decreased transactivation ability in vitro. A p.I263V mutation in TLL1 was identified in an atrial septal defects kindred and is predicted to affect the enzymatic functionality of TLL1. A disease-segregating splice donor site mutation in MYH11 (c.4599+1delG) was identified in familial patent ductus arteriosus and found to disrupt normal splicing of MYH11 mRNA in the affected individual. Our findings demonstrate the clinical utility of WES to identify causative mutations in familial CHD and demonstrate the successful use of a CHD candidate gene list to allow for a more streamlined approach enabling rapid prioritization and identification of likely pathogenic variants from large WES data sets. URL: https://clinicaltrials.gov; Unique Identifier: NCT0112048.

A gain-of-function ACTC1 3'UTR mutation that introduces a miR-139-5p target site may be associated with a dominant familial atrial septal defect.

The ostium secundum atrial septal defect (ASDII) is the most common type of congenital heart disease and is characterized by a left to right shunting of oxygenated blood caused by incomplete closure of the septum secundum. We identified a familial form of isolated ASDII that affects four individuals in a family of five and shows autosomal dominant inheritance. By whole genome sequencing, we discovered a new mutation (c.*1784T > C) in the 3′-untranslated region (3′UTR) of ACTC1, which encodes the predominant actin in the embryonic heart. Further analysis demonstrated that the c.*1784T > C mutation results in a new target site for miRNA-139-5p, a microRNA that is involved in cell migration, invasion, and proliferation. Functional analysis demonstrated that the c.*1784T > C mutation specifically downregulates gene expression in a luciferase assay. Additionally, miR-139-5p mimic causes further decrease, whereas miR-139-5p inhibitor can dramatically rescue the decline in gene expression caused by this mutation. These findings suggest that the familial ASDII may be a result of an ACTC1 3′UTR gain-of-function mutation caused by the introduction of a new miR-139-5p target site. Our results provide the first evidence of a pathogenic mutation in the ACTC1 3′UTR that may be associated with familial isolated ASDII.

Familial Atrial Septal Defect and Sudden Cardiac Death: Identification of a Novel NKX2-5 Mutation and a Review of the Literature.

ObjectiveAtrial septal defect (ASD) is the second most common congenital heart defect (CHD) and is observed in families as an autosomal dominant trait as well as in nonfamilial CHD. Mutations in the NKX2‐5 gene, located on chromosome 5, are associated with ASD, often combined with conduction disturbances, cardiomyopathies, complex CHD, and sudden cardiac death as well. Here, we show that NKX2‐5 mutations primarily occur in ASD patients with conduction disturbances and heritable ASD. Furthermore, these families are at increased risk of sudden cardiac death.ResultsWe screened 39 probands with familial CHD for mutations in NKX2‐5 and discovered a novel mutation in one family (2.5%) with ASD and atrioventricular block. A review of the literature revealed 59 different NKX2‐5 mutations in 202 patients. Mutations were significantly more common in familial cases compared to nonfamilial cases (P = 7.1 × 10−9). The majority of patients (74%) had ASD with conduction disturbance. Nineteen patients (15%) of 120 with familial ASD and conduction disturbance died from sudden cardiac death of which nine (8%) were confirmed mutation carriers, and 10 were possible carriers.Conclusions NKX2‐5 mutations mainly occur in familial CHD, the signature phenotype is ASD with conduction disturbances and mutation carriers are at increased risk of sudden cardiac death. We suggest that familial ASD patients should be screened for NKX2‐5 mutations and, if they are mutation carriers, implantation of an implantable cardioverter‐defibrillator should be considered in these patients.

A novel mutation of GATA4 (K300T) associated with familial atrial septal defect

The GATA-binding protein 4 gene (GATA4) encodes a zinc-finger transcription factor that plays a key role in embryogenesis and cardiac development. Variants in the GATA4 gene have been implicated in several congenital heart diseases (CHD), such as the tetralogy of Fallot (ToF), atrial septal defect (ASD), ventricular septal defect (VSD), atrioventricular septal defect (AVSD), and dilated cardiomyopathy (DCM). We studied a four-generation Chinese ASD family and identified a novel GATA4 mutation (c.A899C, p.K300T) in all surviving affected members and two carriers with incomplete penetrance. Bioinformatics programs (PolyPhen-2, SIFT, and MutationTaster) predicted the mutation to be deleterious. The lysine at the mutation position was highly conserved from Drosophila to humans and was recognized as a methylation location in the GATA4 protein. The involvement of the lysine methylation in cardiogenesis by attenuating the transcriptional activity of GATA4 in mice has been previously examined. Our study broadens the mutation spectrum of the GATA4 gene and reveals for the first time a mutation at the methylation position of GATA4 associated with ASD.

Ultrastructural analysis of the contractile apparatus in the rat’s heart on the stages of ontogeny.

Background. Cardiovascular disease is a major cause of human mortality and disability at working age. Many disorders of cardiac sarcomeres components have been linked to human cardiomyopathies, including desminopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, familial atrial septal defects, and others. Objective. The aim of this work was to determine the remodeling of the contractile apparatus in cardiomyocytes in rat ventricular myocardium on the stages of ontogeny. Methods. White rats were used as a material. Hearts were investigated by the transmission electron microscopy during the stages of prenatal and postnatal ontogeny. Results. Active myofibrilogenesis observed at 18th day of development and dominated in the right ventricle of myocardium during fetal development. After birth there was alignment of myofibrils content in the myocardium of both ventricles. Rapid growth of myofibrils content was seen in the sarcoplasm of cardiomyocytes, which took priority of development in the left ventricle during the period from the 3rd to the 14th day of postnatal ontogeny. At 30th day after the birth the contractile apparatus in the rat’s ventricular myocardium acquired signs of maturity. Conclusion. Development of the contractile apparatus in the rat’s ventricular myocardium is nonlinear and depends on the functional load of heart chamber.

Exome Sequencing Identifies a Novel Variant in ACTC1 Associated With Familial Atrial Septal Defect

BackgroundThe genetics of congenital heart disease (CHD) remain incompletely understood. Exome sequencing has been successfully used to identify disease-causing mutations in familial disorders in which candidate gene analyses and linkage mapping have failed. MethodsWe studied a large family characterized by autosomal dominant isolated secundum atrial septal defect (ASD) (MIM No. 612794). Candidate gene resequencing and linkage analysis were uninformative. ResultsWhole-exome sequencing of 2 affected family members identified 44 rare shared variants, including a nonsynonymous mutation (c.532A>T, p.M178L, NM_005159.4) in alpha-cardiac actin (ACTC1). This mutation was absent from 1834 internal controls as well as from the 1000 Genomes and the Exome Sequencing Project (ESP) databases, but predictions regarding its effect on protein function were divergent. However, p.M178L was the only rare mutation segregating with disease in our family. ConclusionsOur results provide further evidence supporting a causative role for ACTC1 mutations in ASD. Massively parallel sequencing of the exome allows for the detection of novel rare variants causing CHD without the limitations of a candidate gene approach. When mutation prediction algorithms are not helpful, studies of familial disease can help distinguish rare pathologic mutations from benign variants. Consideration of the family history can lead to genetic insights into CHD.

A novel mutation of GATA4 (K319E) is responsible for familial atrial septal defect and pulmonary valve stenosis

Congenital heart disease (CHD) is the most common birth defect in humans, and the etiology of most CHD remains to be elusive. Atrial septal defect (ASD) makes up 30–40% of all adult CHDs and is thought to be genetically heterogeneous. Previous studies have demonstrated that mutations in transcription factors e.g. NKX2.5, GATA4, and TBX5 contribute to congenital ASD. In this study, we investigate a family of three generations with seven patients with ASD and pulmonary valve stenosis (PS). A novel GATA4 mutation, c.955A>G (p.K319E), was identified and co-segregated with the affected patients in this family. This mutation was predicted to be deleterious by three different bioinformatics programs (The polyphen2, SIFT and MutationTaster). Our finding expands the spectrum of GATA4 mutations and provides additional support that GATA4 plays important roles in cardiac development.