Haploinsufficiency of the basic helix–loop–helix transcription factor HAND2 causes congenital heart defects

Ana S.A. Cohen, Christopher Simotas, Bryn D. Webb, Huanzhi Shi, Wahab A. Khan, Lisa Edelmann, Stuart A. Scott, Ram Singh

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Congenital heart defects (CHDs) are caused by a disruption in heart morphogenesis, which is dependent, in part, on a network of transcription factors (TFs) that regulate myocardial development. Heterozygous sequence variants in the basic helix–loop–helix TF gene heart and neural crest derivatives expressed 2 (HAND2) have been reported among some patients with CHDs; however, HAND2 has not yet been established as a Mendelian disease gene. We report a 31-month-old male with unicommissural unicuspid aortic valve, moderate aortic stenosis, and mild pulmonic stenosis. Chromosome analysis revealed a normal 46,XY karyotype, and a CHD sequencing panel was negative for pathogenic variants in NKX2.5, GATA4, TBX5, and CHD7. However, chromosomal microarray (CMA) testing identified a heterozygous 546.0-kb deletion on chromosome 4q34.1 (174364195_174910239[GRCh37/hg19]) that included exons 1 and 2 of SCRG1, HAND2, and HAND2-AS1. Familial CMA testing determined that the deletion was paternally inherited, which supported a likely pathogenic classification as the proband's father had previously undergone surgery for Tetralogy of Fallot. The family history was also notable for a paternal uncle who had previously died from complications related to an unknown heart defect. Taken together, this first report of a HAND2 and HAND2-AS1 deletion in a family with CHDs strongly supports haploinsufficiency of HAND2 as an autosomal dominant cause of CHD.

Original languageEnglish
Pages (from-to)1263-1267
Number of pages5
JournalAmerican Journal of Medical Genetics, Part A
Issue number5
StatePublished - 1 May 2020


  • HAND2
  • Tetralogy of Fallot
  • chromosomal microarray
  • congenital heart defects
  • stenosis


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