title: A novel HAND2 loss-of-function mutation responsible for tetralogy of Fallot.
abstract: Congenital heart disease (CHD), the most common type of developmental abnormality, is associated with substantial morbidity and mortality in humans worldwide. The basic helix-loop-helix transcription factor, heart and neural crest derivatives expressed 2 (HAND2), has been demonstrated to be crucial for normal cardiovascular development in animal models. However, whether a genetically defective HAND2 contributes to congenital heart disease (CHD) in humans remains to be explored. In this study, the entire coding region and splicing boundaries of the HAND2 gene were sequenced in a cohort of 145 unrelated patients with CHD. A total of 200 unrelated, ethnically-matched healthy individuals used as controls were also genotyped for HAND2. The functional effect of the mutant HAND2 was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. As a result, a novel heterozygous HAND2 mutation, p.L47P, was identified in a patient with tetralogy of Fallot (TOF). The misense mutation, which altered the amino acid conserved evolutionarily among species, was absent in 400 control chromosomes. Functional analyses unveiled that the mutant HAND2 had a significantly decreased transcriptional activity. Furthermore, the mutation markedly reduced the synergistic activation between HAND2 and GATA4 or NKX2.5, other two cardiac key transcription factors involved in the pathogenesis of CHD. To the best of our knowledge, this study is the first to report the association of a HAND2 loss-of-function mutation with an increased vulnerability to TOF in humans, which provides novel insight into the molecular mechanism underpinning CHD, suggesting potential implications for the genetic counseling of families with CHD.
authors.affiliation: Department of Pediatrics, Huashan Hospital North, Fudan University, Shanghai 201907, P.R. China.
authors.forename: Cai-Xia
authors.initials: CX
authors.lastname: Lu
authors.affiliation: Department of Pediatrics, Huashan Hospital North, Fudan University, Shanghai 201907, P.R. China.
authors.forename: Hai-Rong
authors.initials: HR
authors.lastname: Gong
authors.affiliation: Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
authors.forename: Xing-Yuan
authors.initials: XY
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
authors.forename: Cui-Mei
authors.initials: CM
authors.lastname: Zhao
authors.affiliation: Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China.
authors.forename: Ri-Tai
authors.initials: RT
authors.lastname: Huang
authors.affiliation: Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China.
authors.forename: Song
authors.initials: S
authors.lastname: Xue
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Yi-Qing
authors.initials: YQ
authors.lastname: Yang
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D013771:Tetralogy of Fallot / Q000235:genetics* / Q000473:pathology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C498765:HAND2 protein, human