TY - JOUR
T1 - Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS
AU - Zhao, Yingjie
AU - Wang, Yujue
AU - Shi, Lijie
AU - McDonald-McGinn, Donna M.
AU - Crowley, T. Blaine
AU - McGinn, Daniel E.
AU - Tran, Oanh T.
AU - Miller, Daniella
AU - Lin, Jhih Rong
AU - Zackai, Elaine
AU - Johnston, H. Richard
AU - Chow, Eva W.C.
AU - Vorstman, Jacob A.S.
AU - Vingerhoets, Claudia
AU - van Amelsvoort, Therese
AU - Gothelf, Doron
AU - Swillen, Ann
AU - Breckpot, Jeroen
AU - Vermeesch, Joris R.
AU - Eliez, Stephan
AU - Schneider, Maude
AU - van den Bree, Marianne B.M.
AU - Owen, Michael J.
AU - Kates, Wendy R.
AU - Repetto, Gabriela M.
AU - Shashi, Vandana
AU - Schoch, Kelly
AU - Bearden, Carrie E.
AU - Digilio, M. Cristina
AU - Unolt, Marta
AU - Putotto, Carolina
AU - Marino, Bruno
AU - Pontillo, Maria
AU - Armando, Marco
AU - Vicari, Stefano
AU - Angkustsiri, Kathleen
AU - Campbell, Linda
AU - Busa, Tiffany
AU - Heine-Suñer, Damian
AU - Murphy, Kieran C.
AU - Murphy, Declan
AU - García-Miñaúr, Sixto
AU - Fernández, Luis
AU - Zhang, Zhengdong D.
AU - Goldmuntz, Elizabeth
AU - Gur, Raquel E.
AU - Emanuel, Beverly S.
AU - Zheng, Deyou
AU - Marshall, Christian R.
AU - International 22q11.2 Brain and Behavior Consortium (IBBC)
AU - Morrow, B.E.
N1 - Funding Information:
The authors declare no competing financial interests. There are competing non-financial interests for JASV and MJO. JASV has served as a consultant for NoBias Therapeutics, Inc for the design of a medication trial for individuals with 22q11DS (unrelated to the content of this work). MJO reports a research grant from Takeda Pharmaceuticals outside the scope of the current work. The remaining authors declare no competing interests.
Funding Information:
We acknowledge support from the Genomics and Epigenomics Core facilities at Einstein. This work was supported by a Leducq Foundation grant and NIH grants P01HD070454, R01HL157157, R01GM125757 and U01MH101720. National Institute for Mental Health (MBMvdB, 5U01MH101724). D.H.S. has been funded by Instituto de Salud Carlos III through the project “PI18/00847” (co-funded by the European Regional Development Fund/European Social Fund’s “A way to make Europe”/” Investing in your future”). JASV is supported by NIMH grant U01MH119741-01 and SickKids Psychiatry Associates Chair in Developmental Psychopathology. JB is supported by a senior investigator fellowship of FWO Flanders. MJO was supported by Medical Research Council UK, Centre Grant No. MR/L010305/1, Program Grant No. MR/P005748/1. We thank The Centre for Applied Genomics (Toronto, Canada) for informatics expertise. We thank Xianhong Xie for statistical advice. Steven T. Warren was a co-PI of the 22q Sequencing Consortium and significantly contributed to this work prior to his untimely death in June of 2021. We thank Gloria Stoyanova for the help with generating the STRING figure.
Funding Information:
We acknowledge support from the Genomics and Epigenomics Core facilities at Einstein. This work was supported by a Leducq Foundation grant and NIH grants P01HD070454, R01HL157157, R01GM125757 and U01MH101720. National Institute for Mental Health (MBMvdB, 5U01MH101724). D.H.S. has been funded by Instituto de Salud Carlos III through the project “PI18/00847” (co-funded by the European Regional Development Fund/European Social Fund’s “A way to make Europe”/” Investing in your future”). JASV is supported by NIMH grant U01MH119741-01 and SickKids Psychiatry Associates Chair in Developmental Psychopathology. JB is supported by a senior investigator fellowship of FWO Flanders. MJO was supported by Medical Research Council UK, Centre Grant No. MR/L010305/1, Program Grant No. MR/P005748/1. We thank The Centre for Applied Genomics (Toronto, Canada) for informatics expertise. We thank Xianhong Xie for statistical advice. Steven T. Warren was a co-PI of the 22q Sequencing Consortium and significantly contributed to this work prior to his untimely death in June of 2021. We thank Gloria Stoyanova for the help with generating the STRING figure.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/7/18
Y1 - 2023/7/18
N2 - 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.
AB - 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.
U2 - 10.1038/s41525-023-00363-y
DO - 10.1038/s41525-023-00363-y
M3 - Article
C2 - 37463940
SN - 2056-7944
VL - 8
JO - npj Genomic Medicine
JF - npj Genomic Medicine
IS - 1
M1 - 17
ER -