NKX2-5 Mutations in an Inbred Consanguineous Population: Genetic and Phenotypic Diversity

Hassan, Ossama K. Abou; Fahed, Akl C.; Batrawi, Manal; Arabi, Mariam; Refaat, Marwan M.; DePalma, Steven R.; Seidman, Jonathan G.; Seidman, Christine E.; Bitar, Fadi; Nemer, Georges

doi:10.1038/srep08848

Cited by 44 publications

(25 citation statements)

References 52 publications

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“…The remaining 10 patients were all part of pedigrees with dominant traits of NKX2-5 mutations co-segregating with the malformations, and they all died suddenly before the age of 50. Assuming that these 10 were carriers of the mutations transmitted in their families, the total number of patients with familial ASD with CD/A would be 130 (112 1 8 obligate 110 possible carriers), 46 25 (3) corresponding to SCDs in 8% of mutation carriers with familial ASD and CD/A and 15% if the possible carriers are included. There were no sudden deaths reported in the nonfamilial cases.…”

Section: Scd Occurred In 15% Of Patients With Familial Asd and Cd/amentioning

confidence: 99%

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Familial Atrial Septal Defect and Sudden Cardiac Death: Identification of a NovelNKX2-5Mutation and a Review of the Literature

Ellesøe

Johansen

Bjerre

et al. 2015

Congenital Heart Disease

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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.

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Section: Scd Occurred In 15% Of Patients With Familial Asd and Cd/amentioning

confidence: 99%

“…Figure IV. Pedigrees from published papers reporting sudden cardiac deaths: Abou Hassan et al (2015) …”

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confidence: 99%

Familial Atrial Septal Defect and Sudden Cardiac Death: Identification of a NovelNKX2-5Mutation and a Review of the Literature

Ellesøe

Johansen

Bjerre

et al. 2015

Congenital Heart Disease

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“…NKX2-5, a homeodomain transcription factor expressed in cells of the FHF and SHF (Stanley et al, 2002), and a regulator of cardiac development (Bruneau, 2008), is associated with a myriad of human CHDs. Moreover, individuals carrying NKX2-5 mutations demonstrate a propensity to develop malformations involving the poles of the heart, such as Tetralogy of Fallot, double outlet right ventricle and atrial septal defects (Abou Hassan et al, 2015;Benson et al, 1999;Chung and Rajakumar, 2016;Elliott et al, 2003;Goldmuntz et al, 2001;McElhinney et al, 2003;Nakajima, 2010;Schott et al, 1998;Srivastava and Olson, 2000). Investigation of the genetic basis of CHDs in model systems has yielded insights into functions of Nkx2-5 in progenitor specification in Drosophila, Xenopus and mouse (Azpiazu and Frasch, 1993;Bodmer, 1993;Grow and Krieg, 1998;Prall et al, 2007), and in cardiac morphogenesis in mouse and zebrafish (Barth et al, 2010;Lyons et al, 1995;Prall et al, 2007;Tanaka et al, 1999;Targoff et al, 2013Targoff et al, , 2008Tu et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

nkxgenes establish SHF cardiomyocyte progenitors at the arterial pole and pattern the venous pole through Isl1 repression

et al. 2017

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is the most commonly mutated gene associated with human congenital heart defects (CHDs), with a predilection for cardiac pole abnormalities. This homeodomain transcription factor is a central regulator of cardiac development and is expressed in both the first and second heart fields (FHF and SHF). We have previously revealed essential functions of and, two homologs expressed in zebrafish cardiomyocytes, in maintaining ventricular identity. However, the differential roles of these genes in the specific subpopulations of the anterior (aSHF) and posterior (pSHF) SHFs have yet to be fully defined. Here, we show that Nkx genes regulate aSHF and pSHF progenitors through independent mechanisms. We demonstrate that Nkx genes restrict proliferation of aSHF progenitors in the outflow tract, delimit the number of pSHF progenitors at the venous pole and pattern the sinoatrial node acting through Isl1 repression. Moreover, optical mapping highlights the requirement for Nkx gene dose in establishing electrophysiological chamber identity and in integrating the physiological connectivity of FHF and SHF cardiomyocytes. Ultimately, our results may shed light on the discrete errors responsible for-dependent human CHDs of the cardiac outflow and inflow tracts.

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“…By contrast, mice homozygous for a ventricle-restricted knockout of Nkx2.5 showed no cardiovascular structural defects, but exhibited marked overgrowth of trabecular muscle and progressive complete heart block owing to hypoplastic atrioventricular node at birth (38). In humans, mutations in NKX2.5 have been associated with a wide spectrum of cardiovascular diseases, including congenital heart defects, such as atrial septal defect (ASD), ventricular septal defect, tetralogy of Fallot, bicuspid aortic valve, mitral valve deformations, subvalvular aortic stenosis, abnormal systemic venous return, hypoplasia of left heart and visceral situs inversus (2,(5)(6)(7)(8)(9)39), dilated cardiomyopathy (10), arrhythmias, such as atrioventricular block (AVB), atrial fibrillation and ventricular tachycardia (10)(11)(12)34,(40)(41)(42), and sudden cardiac death (12,43,44), of which ASD and AVB are the two most frequent phenotypes in patients carrying NKX2.5 mutations. Of note, in a murine knock-in model generated by knocking in a comparable NKX2.5 missense mutation (p.R52G) previously identified in patients, pleiotropic cardiac anomalies, including ASD, ventricular septal defect, atrioventricular septal defect, Ebstein malformation of the tricuspid valve and ventricular noncompaction were observed, in addition to progressive AVB, and this was similar or more marked, compared with the cardiac anomalies found in humans harboring a heterozygous mutation of p.R52 G in NKX2.5 (45,46).…”

Section: Prevalence and Spectrum Of Nkx25 Mutations In Patients Withmentioning

confidence: 99%

Prevalence and spectrum of NKX2.5 mutations in patients with congenital atrial septal defect and atrioventricular block

Qiu

Fang

et al. 2017

Molecular Medicine Reports

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Congenital atrial septal defect (ASD) and progressive atriventricular block (AVB) are the two most common phenotypes linked to NK2 homeobox 5 (NKX2.5) mutations in animals and humans. However, the prevalence and spectrum of NKX2.5 mutation in patients with ASD and AVB remain to be elucidated. In the present study, the coding exons and flanking introns of the NKX2.5 gene, which encodes a homeobox‑containing transcription factor essential for development of the heart, were sequenced in a cohort of 62 unrelated patients with ASD and AVB, and subsequently in a mutation carrier's available family members. As controls, 300 unrelated, ethnically‑matched healthy individuals were recruited, who were also genotyped for NKX2.5. The functional consequence of the mutant NKX2.5 was evaluated in contrast to its wild‑type counterpart using a dual‑luciferase reporter assay system. As a result, a novel heterozygous NKX2.5 mutation, p.Q181X, was identified in an index patient with ASD and AVB, with a prevalence of ~1.61%. Genetic analysis of the proband's pedigree revealed that the mutation co‑segregated with ASD and AVB with complete penetrance. The nonsense mutation, which eliminated partial homeobox and the carboxyl terminus, was absent in the 600 control chromosomes. Functional evaluation showed that the NKX2.5 mutant had no transcriptional activity. Furthermore, the mutation disrupted the synergistic activation between NKX2.5 and GATA binding protein 4, another cardiac core transcription factor associated with ASD. The results of the present study expand the spectrum of NKX2.5 mutations linked to ASD and AVB, and indicated that NKX2.5 loss‑of‑function mutations are an uncommon cause of ASD and AVB in humans.

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NKX2-5 Mutations in an Inbred Consanguineous Population: Genetic and Phenotypic Diversity

Cited by 44 publications

References 52 publications

Familial Atrial Septal Defect and Sudden Cardiac Death: Identification of a NovelNKX2-5Mutation and a Review of the Literature

Familial Atrial Septal Defect and Sudden Cardiac Death: Identification of a NovelNKX2-5Mutation and a Review of the Literature

nkxgenes establish SHF cardiomyocyte progenitors at the arterial pole and pattern the venous pole through Isl1 repression

Prevalence and spectrum of NKX2.5 mutations in patients with congenital atrial septal defect and atrioventricular block

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