title: Novel NKX2-5 mutations  responsible for congenital heart disease.
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.
authors.affiliation: Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: X Y
authors.initials: XY
authors.lastname: Liu
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Yang
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005799:Genes, Dominant; D056726:Genetic Association Studies; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics*; D006579:Heterozygote; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009206:Myocardium / Q000473:pathology*; D016366:Open Reading Frames; D010375:Pedigree; D019683:Penetrance; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D014157:Transcription Factors