HGG Advances (Jul 2021)
Common deletion variants causing protocadherin-α deficiency contribute to the complex genetics of BAV and left-sided congenital heart disease
- Polakit Teekakirikul,
- Wenjuan Zhu,
- George C. Gabriel,
- Cullen B. Young,
- Kylia Williams,
- Lisa J. Martin,
- Jennifer C. Hill,
- Tara Richards,
- Marie Billaud,
- Julie A. Phillippi,
- Jianbin Wang,
- Yijen Wu,
- Tuantuan Tan,
- William Devine,
- Jiuann-huey Lin,
- Abha S. Bais,
- Jonathan Klonowski,
- Anne Moreau de Bellaing,
- Ankur Saini,
- Michael X. Wang,
- Leonid Emerel,
- Nathan Salamacha,
- Samuel K. Wyman,
- Carrie Lee,
- Hung Sing Li,
- Anastasia Miron,
- Jingyu Zhang,
- Jianhua Xing,
- Dennis M. McNamara,
- Erik Fung,
- Paul Kirshbom,
- William Mahle,
- Lazaros K. Kochilas,
- Yihua He,
- Vidu Garg,
- Peter White,
- Kim L. McBride,
- D. Woodrow Benson,
- Thomas G. Gleason,
- Seema Mital,
- Cecilia W. Lo
Affiliations
- Polakit Teekakirikul
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Centre for Cardiovascular Genomics and Medicine, Division of Cardiology, and Division of Medical Sciences, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong SAR, China
- Wenjuan Zhu
- Centre for Cardiovascular Genomics and Medicine, Division of Cardiology, and Division of Medical Sciences, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong SAR, China
- George C. Gabriel
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Cullen B. Young
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Kylia Williams
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Lisa J. Martin
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, and Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, USA
- Jennifer C. Hill
- Department of Cardiothoracic Surgery and Department of Bioengineering, McGowan Institute for Regenerative Medicine, and Center for Vascular Remodeling and Regeneration, University of Pittsburgh, Pittsburgh, PA, USA
- Tara Richards
- Department of Cardiothoracic Surgery and Department of Bioengineering, McGowan Institute for Regenerative Medicine, and Center for Vascular Remodeling and Regeneration, University of Pittsburgh, Pittsburgh, PA, USA
- Marie Billaud
- Department of Cardiothoracic Surgery and Department of Bioengineering, McGowan Institute for Regenerative Medicine, and Center for Vascular Remodeling and Regeneration, University of Pittsburgh, Pittsburgh, PA, USA
- Julie A. Phillippi
- Department of Cardiothoracic Surgery and Department of Bioengineering, McGowan Institute for Regenerative Medicine, and Center for Vascular Remodeling and Regeneration, University of Pittsburgh, Pittsburgh, PA, USA
- Jianbin Wang
- School of Life Sciences, Tsinghua University, Beijing, China
- Yijen Wu
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Tuantuan Tan
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- William Devine
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Jiuann-huey Lin
- Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Abha S. Bais
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Jonathan Klonowski
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Anne Moreau de Bellaing
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Pediatric Cardiology, Necker-Sick Children Hospital and University of Paris Descartes, Paris, France
- Ankur Saini
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Michael X. Wang
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Leonid Emerel
- Department of Cardiothoracic Surgery and Department of Bioengineering, McGowan Institute for Regenerative Medicine, and Center for Vascular Remodeling and Regeneration, University of Pittsburgh, Pittsburgh, PA, USA
- Nathan Salamacha
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Samuel K. Wyman
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Carrie Lee
- Centre for Cardiovascular Genomics and Medicine, Division of Cardiology, and Division of Medical Sciences, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong SAR, China
- Hung Sing Li
- Centre for Cardiovascular Genomics and Medicine, Division of Cardiology, and Division of Medical Sciences, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong SAR, China
- Anastasia Miron
- Division of Cardiology, Labatt Family Heart Centre, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
- Jingyu Zhang
- Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Jianhua Xing
- Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Dennis M. McNamara
- Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Erik Fung
- Centre for Cardiovascular Genomics and Medicine, Division of Cardiology, and Division of Medical Sciences, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong SAR, China; Laboratory for Heart Failure and Circulation Research, Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, CARE Programme, Lui Che Woo Institute of Innovative Medicine, and Gerald Choa Cardiac Research Centre, Chinese University of Hong Kong, Hong Kong SAR, China
- Paul Kirshbom
- Sanger Heart & Vascular Institute, Charlotte, NC, USA
- William Mahle
- Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA, USA
- Lazaros K. Kochilas
- Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA, USA
- Yihua He
- Department of Ultrasound, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- Vidu Garg
- Center for Cardiovascular Research, The Heart Center, Nationwide Children’s Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
- Peter White
- The Institute for Genomic Medicine, Center for Cardiovascular Research, Nationwide Children’s Hospital and Department of Pediatrics, Ohio State University College of Medicine, Columbus, OH, USA
- Kim L. McBride
- Center for Cardiovascular Research, The Heart Center, Nationwide Children’s Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
- D. Woodrow Benson
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
- Thomas G. Gleason
- Division of Cardiac Surgery, Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
- Seema Mital
- Division of Cardiology, Labatt Family Heart Centre, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
- Cecilia W. Lo
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Corresponding author
- Journal volume & issue
-
Vol. 2,
no. 3
p. 100037
Abstract
Summary: Bicuspid aortic valve (BAV) with ∼1%–2% prevalence is the most common congenital heart defect (CHD). It frequently results in valve disease and aorta dilation and is a major cause of adult cardiac surgery. BAV is genetically linked to rare left-heart obstructions (left ventricular outflow tract obstructions [LVOTOs]), including hypoplastic left heart syndrome (HLHS) and coarctation of the aorta (CoA). Mouse and human studies indicate LVOTO is genetically heterogeneous with a complex genetic etiology. Homozygous mutation in the Pcdha protocadherin gene cluster in mice can cause BAV, and also HLHS and other LVOTO phenotypes when accompanied by a second mutation. Here we show two common deletion copy number variants (delCNVs) within the PCDHA gene cluster are associated with LVOTO. Analysis of 1,218 white individuals with LVOTO versus 463 disease-free local control individuals yielded odds ratios (ORs) at 1.47 (95% confidence interval [CI], 1.13–1.92; p = 4.2 × 10−3) for LVOTO, 1.47 (95% CI, 1.10–1.97; p = 0.01) for BAV, 6.13 (95% CI, 2.75–13.7; p = 9.7 × 10−6) for CoA, and 1.49 (95% CI, 1.07–2.08; p = 0.019) for HLHS. Increased OR was observed for all LVOTO phenotypes in homozygous or compound heterozygous PCDHA delCNV genotype comparison versus wild type. Analysis of an independent white cohort (381 affected individuals, 1,352 control individuals) replicated the PCDHA delCNV association with LVOTO. Generalizability of these findings is suggested by similar observations in Black and Chinese individuals with LVOTO. Analysis of Pcdha mutant mice showed reduced PCDHA expression at regions of cell-cell contact in aortic smooth muscle and cushion mesenchyme, suggesting potential mechanisms for BAV pathogenesis and aortopathy. Together, these findings indicate common variants causing PCDHA deficiency play a significant role in the genetic etiology of common and rare LVOTO-CHD.
