Abstract
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...Continue Reading
References
Jun 1, 1997·Nature Genetics·D SrivastavaE N Olson
Jul 11, 1998·The Journal of Biological Chemistry·M DronM G Tovey
May 8, 2002·The Journal of Biological Chemistry·Yan-Shan DaiJeffery D Molkentin
Dec 9, 2003·Trends in Molecular Medicine·Cathy J HatcherCraig T Basson
May 20, 2005·The Journal of Clinical Investigation·Elisabeth M ZeisbergWilliam T Pu
Nov 15, 2008·Circulation Research·Yuka Morikawa, Peter Cserjesi
Feb 11, 2010·Developmental Biology·Kristen L HollerMarthe J Howard
Oct 27, 2010·PLoS Genetics·Ni HuangMatthew E Hurles
Nov 27, 2010·Genetica·Ting PengXiaotian Li
Aug 1, 2012·American Journal of Medical Genetics. Part a·Eugen-Matthias StrehleTaosheng Huang
Sep 4, 2012·American Journal of Human Genetics·Rachel SoemediBernard D Keavney
Mar 2, 2013·Human Molecular Genetics·Masaru TamuraToshihiko Shiroishi
Nov 1, 2013·Nucleic Acids Research·Jeffrey R MacDonaldStephen W Scherer
Aug 6, 2014·PloS One·Ana TöpfJudith A Goodship
Dec 18, 2015·International Journal of Molecular Medicine·Cai-Xia LuYi-Qing Yang
Feb 13, 2016·G3 : Genes - Genomes - Genetics·Yu-Min SunYi-Qing Yang
Nov 4, 2016·Nature·Kelly M AndersonEric N Olson
Aug 11, 2018·Human Mutation·Erin R RiggsChrista L Martin
Sep 16, 2018·European Journal of Medical Genetics·Hua LiuYi-Qing Yang
Oct 6, 2018·The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology·Rajani M George, Anthony B Firulli
Jul 6, 2019·Development·Xue HanXiaohua Shen