The diagnostic value of next generation sequencing in familial nonsyndromic congenital heart defects

Jia, Yaojuan; Louw, Jacoba; Breckpot, Jeroen; Callewaert, Bert; Barréa, Catherine; Sznajer, Yves; Gewillig, Marc; Souche, Erika; Dehaspe, Luc; Vermeesch, Joris Robert; Lambrechts, Diether; Devriendt, Koenraad; Corveleyn, Anniek

doi:10.1002/ajmg.a.37108

Cited by 49 publications

(51 citation statements)

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“…During the past decade, a number of pathogenic mutations in different genes have been identified in CHD by Sanger sequencing of single genes, TES, or whole-exome sequencing, and new candidate genes and variants were constantly reported in CHD patients [30–33]. In this study, using TES, we designed a twenty-nine gene panel to sequence the coding regions of these candidate genes in 106 sporadic TOF patients.…”

Section: Discussionmentioning

confidence: 99%

Multiple gene variations contributed to congenital heart disease via GATA family transcriptional regulation

et al. 2017

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BackgroundCongenital heart disease (CHD) is a common birth defect, and most cases occur sporadically. Mutations in key genes that are responsible for cardiac development could contribute to CHD. To date, the genetic causes of CHD remain largely unknown.MethodsIn this study, twenty-nine candidate genes in CHD were sequenced in 106 patients with Tetralogy of Fallot (TOF) using target exome sequencing (TES). The co-immunoprecipitation (CO-IP) and luciferase reporter gene assays were performed in HEK293T cells, and wild-type and mutant mRNA of ZFPM2 were microinjected into zebrafish embryos.ResultsRare variants in key cardiac transcriptional factors and JAG1 were identified in the patients. Four patients carried multiple gene variants. The novel E1148K variant was located at the eighth Zinc-finger domain of FOG2 protein. The CO-IP assays in the HEK293T cells revealed that the variant significantly damaged the interaction between ZFPM2/FOG2 and GATA4. The luciferase reporter gene assays revealed that the E1148K mutant ZFPM2 protein displayed a significantly greater inhibition of the transcriptional activation of GATA4 than the wild-type protein. The wild-type mRNA and the E1148K mutant mRNA of ZFPM2 were injected into zebrafish embryos. At 48 hpf, in the mutant mRNA injection group, the number of embryos with an abnormal cardiac chamber structure and a loss of left–right asymmetry was increased. By 72 hpf, the defects in the chamber and left–right asymmetry became obvious.ConclusionsWe performed TES in sporadic TOF patients and identified rare variants in candidate genes in CHD. We first validated the E1148 K variant in ZFPM2, which is likely involved in the pathogenesis of CHD via GATA4. Moreover, our results suggest that TES could be a useful tool for discovering sequence variants in CHD patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1173-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Multiple gene variations contributed to congenital heart disease via GATA family transcriptional regulation

et al. 2017

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“…Targeted sequencing is being offered for panels of CHD candidate genes. Two studies using similar sets of 57 genes previously implicated in CHD to test a group of patients from non-syndromic CHD families with probable dominantly inherited CHD identified likely causative mutations in 25–46% of the families 148, 149 . This approach relies on variants segregating with disease within a family, and thus becomes more difficult in non-familial CHD, first because the composition of the currently utilized CHD gene sets in the targeted sequencing approach are biased towards inherited CHD, and second because variant interpretation in an isolated case is more challenging.…”

Section: Clinical Impact Of Chd Geneticsmentioning

confidence: 99%

Genetics and Genomics of Congenital Heart Disease

Zaidi

Brueckner

2017

Circulation Research

390

432

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Congenital heart disease is the most common birth defect, and due to major advances in medical and surgical management, there are now more adults living with CHD than children. Until recently, the cause of the majority of CHD was unknown. Advances in genomic technologies have discovered the genetic etiology of a significant fraction of CHD, while at the same time pointing to remarkable complexity in CHD genetics. This review will focus on the evidence for genetic causes underlying CHD and discuss data supporting both monogenic and complex genetic mechanisms underlying CHD. The discoveries from CHD genetic studies draw attention to biological pathways that simultaneously open the door to a better understanding of cardiac development, and impact clinical care of CHD patients. Finally, we address clinical genetic evaluation of patients and families affected by CHD.

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“…However, considering the low incidence of TAPVAR in population, our study is still a good attempt. In addition, analysis only focused on variations in coding regions, information for other regions were missing (such as introns, UTR or intergenic regions) [21]. Taken together, our findings need to be further validated in functional studies or large well-designed population-based studies in the future.…”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing identifies SGCD and ACVRL1 mutations associated with total anomalous pulmonary venous return (TAPVR) in Chinese population

Yang

et al. 2017

Oncotarget

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As a rare type of Congenital Heart Defects (CHD), the genetic mechanism of Total Anomalous Pulmonary Venous Return (TAPVR) remains unknown, although previous studies have revealed potential disease-driving regions/genes. Blood samples collected from the 6 sporadic TAPVR cases and 81 non-TAPVR controls were subjected to whole exome sequencing. All detected variations were confirmed by direct Sanger sequencing. Here, we identified 2 non-synonymous missense mutations: c.C652T, p.R218W in activin A receptor type II-like 1 (ACVRL1), c.C717G, p.D239E in sarcoglycan delta (SGCD). Our results offered the landscape of mutations for TAPVR in Chinese population firstly and are valuable in the mutation-based pre- and post-natal screening and genetic diagnosis for TAPVR.

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The diagnostic value of next generation sequencing in familial nonsyndromic congenital heart defects

Cited by 49 publications

References 35 publications

Multiple gene variations contributed to congenital heart disease via GATA family transcriptional regulation

Multiple gene variations contributed to congenital heart disease via GATA family transcriptional regulation

Genetics and Genomics of Congenital Heart Disease

Whole-exome sequencing identifies SGCD and ACVRL1 mutations associated with total anomalous pulmonary venous return (TAPVR) in Chinese population

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