Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS

• Authors: Yingjie Zhao, Albert Einstein College of Medicine; Yujue Wang, Albert Einstein College of Medicine; Lijie Shi, Albert Einstein College of Medicine; Donna M McDonald-McGinn, University of Pennsylvania; T. Blaine Crowley, University of Pennsylvania; Daniel E McGinn, University of Pennsylvania; Oanh T Tran, University of Pennsylvania; Daniella Miller, Albert Einstein College of Medicine; Jhih-Rong Lin, Albert Einstein College of Medicine; Elaine Zackai, University of Pennsylvania; H. Richard Johnston, Emory University; Eva W. C Chow, University of Toronto; Jacob A. S Vorstman, Hospital for Sick Children, Toronto; Claudia Vingerhoets, Maastricht University; Therese van Amelsvoort, Maastricht University; Doron Gothelf, Tel Aviv University; Ann Swillen, University of Leuven; Jeroen Breckpot, University of Leuven; Joris R Vermeesch, University of Leuven; Stephan Eliez, University of Geneva; Maude Schneider, University of Geneva; Marianne B. M van den Bree, Cardiff University; Michael J Owen, Cardiff University; Wendy R Kates, SUNY Upstate Medical University; Gabriela M Repetto, Alemana-Universidad del Desarrollo; Vandana Shashi, Duke University; Kelly Schoch, Duke University; Carrie E Bearden, University of California Los Angeles; M. Cristina Digilio, Bambino Gesù Hospital, Rome; Marta Unolt, Bambino Gesù Hospital, Rome; Carolina Putotto, La Sapienza University of Rome; Bruno Marino, La Sapienza University of Rome; Maria Pontillo, Bambino Gesù Hospital, Rome; Marco Armando, Bambino Gesù Hospital, Rome; Stefano Vicari, Catholic University, Rome; Kathleen Angkustsiri, University of California Davis; Linda Campbell, University of Newcastle; Tiffany Busa, Aix-Marseille University; Damian Heine-Suner, Son Espases University Hospital, Spain; Kieran C Murphy, Royal College of Surgeons in Ireland; Declan Murphy, King’s College London; Sixto Garcia-Minaur, Hospital Universitario La Paz; Luis Fernandez, Hospital Universitario La Paz; Zhengdong D Zhang, Albert Einstein College of Medicine; Elizabeth Goldmuntz, Childrens Hospital of Philadelphia; Raquel E Gur, University of Pennsylvania; Beverly S Emanuel, University of Pennsylvania; Deyou Zheng, Albert Einstein College of Medicine; Christian R Marshall, University of Toronto; Anne S Bassett, University of Toronto; Tao Wang, Albert Einstein College of Medicine; Bernice E Morrow, Albert Einstein College of Medicine
• Journal Title: NPJ GENOMIC MEDICINE
• Volume: Volume 8, Number 1
• Publisher: NATURE PORTFOLIO | 2023-07-18, Pages 17-17
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/s41525-023-00363-y
• Subjects: Biology, Genetics; Health Sciences, Pathology; Health Sciences, Public Health; Psychology, Psychobiology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Genetics & Heredity; DE-NOVO MUTATIONS; ESSENTIAL GENES; DISEASE; VARIANTS; PHENOTYPES; FRAMEWORK; PATHWAYS; PACKAGE; FAMILY

Abstract

Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40–50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD.