Mutation in myosin heavy chain 6 causes atrial septal defect

Ching, Yung-Hao; Ghosh, Tushar K.; Cross, Steve J.; Packham, Elizabeth A.; Honeyman, Louise; Loughna, Siobhan; Robinson, Thelma; Dearlove, A M; Ribas, Gloría; Bonser, Andrew J.; Thomas, Neil R.; Scotter, Andrew J; Caves, Leo S. D.; Tyrrell, Graham P.; Newbury‐Ecob, Ruth; Münnich, Arnold; Bonnet, Damien; Brook, David

doi:10.1038/ng1526

Cited by 255 publications

(190 citation statements)

References 28 publications

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“…The cross-species alignment of TBX5 protein showed that the altered tryptophan residue is evolutionarily conserved throughout the vertebrates, indicating its functional importance [22]. The understanding of the genetic mutations is an important aspect in deciphering the consequential clinical phenotypes [23,24]. This study was performed to investigate the basis of this divergent phenotype related to a single gene mutation.…”

Section: Discussionmentioning

confidence: 99%

A Tbx5 Nonsense Mutation in Siblings With Divergent Phenotypes Associated With Isolated Septal Defects

Borkar

Nayak

Shetty

et al. 2017

Asian J Pharm Clin Res

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Objective: Heart septal defects (HSD) account for 50% of the congenital heart malformations and are characterized by the hole in the wall of tissue which separates the heart chambers. The known causes of the SD are multifactorial and complex inheritance.Methods: Isolated 15 subjects with ostium secundum atrial SD (OS-ASD) and one subject with perimembranous ventricular SD (VSD) among 125 clinically diagnosed SD were included in the study. Sanger sequencing was performed for all the exons of TBX5 genes using genomic DNA of these patients.Results: Sequence variation c.444 G>A substitution, leads to the alteration of tryptophan residue into premature stop codon at codon 148. We observed a divergent phenotype within a family of four, where one sibling and the mother had OS-ASD, another sibling had phenotype of perimembranous VSD, and the father had normal genotype. Conclusion:We believe that this novel sequence variant in TBX5 gene is one of the factors in the SD and may hold a key determining the role of TBX5 gene in the heart development.

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Section: Discussionmentioning

confidence: 99%

A Tbx5 Nonsense Mutation in Siblings With Divergent Phenotypes Associated With Isolated Septal Defects

Borkar

Nayak

Shetty

et al. 2017

Asian J Pharm Clin Res

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“…Different congenital heart malformations (septal defects, patent ductus arteriosus, aortic aneurysm, and Ebstein anomaly) have been reported in families with pathogenic mutations in sarcomeric protein genes, including MYBPC3, MYH6, MYH7, MYH11, and ACTC1. 31,[36][37][38] In children with noncompaction cardiomyopathy, Tsai et al 39 showed that 78% had a congenital heart defect. These data suggest that sarcomeric cardiac muscle proteins are not only involved in cardiomyopathies but also in congenital heart malformations.…”

Section: Discussionmentioning

confidence: 99%

Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects

et al. 2014

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Familial hypertrophic cardiomyopathy (HCM) is usually caused by autosomal dominant pathogenic mutations in genes encoding sarcomeric or sarcomere-associated cardiac muscle proteins. The disease mainly affects adults, although young children with severe HCM have also been reported. We describe four unrelated neonates with lethal cardiomyopathy, and performed molecular studies to identify the genetic defect. We also present a literature overview of reported patients with compound heterozygous or homozygous pathogenic MYBPC3 mutations and describe their clinical characteristics. All four children presented with feeding difficulties, failure to thrive, and dyspnea. They died from cardiac failure before age 13 weeks. Features of left ventricular noncompaction were diagnosed in three patients. In the fourth, hypertrabeculation was not a clear feature, but could not be excluded. All of them had septal defects. Two patients were compound heterozygotes for the pathogenic c.2373dup p. (Trp792fs) and c.2827C4T p.(Arg943*) mutations, and two were homozygous for the c.2373dup and c.2827C4T mutations. All patients with biallelic truncating pathogenic mutations in MYBPC3 reported so far (n = 21) were diagnosed with severe cardiomyopathy and/or died within the first few months of life. In 62% (13/21), septal defects or a patent ductus arteriosus accompanied cardiomyopathy. In contrast to heterozygous pathogenic mutations, homozygous or compound heterozygous truncating pathogenic MYBPC3 mutations cause severe neonatal cardiomyopathy with features of left ventricular noncompaction and septal defects in approximately 60% of patients.

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“…Also, mutations in cardiac structural proteins as alpha myosin heavy chain (MYH6) and alpha cardiac actin (ACTC1) were identified in familial CHD (Ching et al, 2005;Matsson et al, 2008). However, so far, only NKX2-5 mutations were reported to cause an atrial septal defect phenotype and development of atrioventricular block (Stallmeyer et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Novel NKX2-5 mutations responsible for congenital heart disease

Wang

Xy²,

Yq³

2011

Genet. Mol. Res.

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ABSTRACT. Congenital heart disease (CHD) is the most common birth defect and is the leading cause of infant morbidity and mortality resulting from birth defects. Increasing evidence demonstrates that genetic variation in the NKX2-5 gene, which encodes a homeobox-containing transcription factor crucial to cardiogenesis, is an important molecular determinant for CHD. Nevertheless, the genetic components underlying CHD remain largely unknown. We screened NKX2-5 for potential molecular defects in patients with CHD. The entire coding region of NKX2-5 was initially sequenced in a cohort of 268 unrelated patients with CHD. The relatives of the patients carrying identified mutations and 200 unrelated control individuals were subsequently genotyped. Three novel heterozygous missense NKX2-5 mutations, p.Q22K, p.R36S, and p.E54K, were identified in three families with autosomal dominantly inherited atrial septal defect, ventricular septal defect, and tetralogy of Fallot, respectively. These mutations, absent in 200 control individuals, appear to be highly conserved evolutionarily and co-segregated with CHD in the families, with complete penetrance. These findings expand the spectrum of mutations in NKX2-5 associated with CHD and provide new insight into the molecular etiology involved in the pathogenesis of CHD, which signifies potential implications for genetic diagnosis and gene-specific therapy for this common disease in newborns.

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Mutation in myosin heavy chain 6 causes atrial septal defect

Cited by 255 publications

References 28 publications

A Tbx5 Nonsense Mutation in Siblings With Divergent Phenotypes Associated With Isolated Septal Defects

A Tbx5 Nonsense Mutation in Siblings With Divergent Phenotypes Associated With Isolated Septal Defects

Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects

Novel NKX2-5 mutations responsible for congenital heart disease

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