TY - JOUR
T1 - Histone Modifier Genes Alter Conotruncal Heart Phenotypes in 22q11.2 Deletion Syndrome
AU - Guo, Tingwei
AU - Chung, Jonathan H.
AU - Wang, Tao
AU - McDonald-Mcginn, Donna M.
AU - Kates, Wendy R.
AU - Hawuła, Wanda
AU - Coleman, Karlene
AU - Zackai, Elaine
AU - Emanuel, Beverly S.
AU - Morrow, Bernice E.
N1 - Funding Information:
We thank Dr. Jidong Shan, Ms. Yinghui Song, and Ms. Debbie Lewis in the Molecular Cytogenetics core lab at Einstein for technical support. We thank Emma Mclaughlin and Eugene Park for their outstanding technical support. We also appreciate the services of the Genomics Core at Einstein for Sanger DNA sequencing analysis. WES services were provided through the RS&G Service by the Northwest Genomics Center at the University of Washington, Department of Genome Sciences, under U.S. Federal Government contract number HHSN268201100037C from the National Heart, Lung, and Blood Institute. This work was supported by grant P01 HD070454 from the NICHD at NIH.
Publisher Copyright:
© 2015 The American Society of Human Genetics.
PY - 2015/12/3
Y1 - 2015/12/3
N2 - We performed whole exome sequence (WES) to identify genetic modifiers on 184 individuals with 22q11.2 deletion syndrome (22q11DS), of whom 89 case subjects had severe congenital heart disease (CHD) and 95 control subjects had normal hearts. Three genes including JMJD1C (jumonji domain containing 1C), RREB1 (Ras responsive element binding protein 1), and SEC24C (SEC24 family member C) had rare (MAF < 0.001) predicted deleterious single-nucleotide variations (rdSNVs) in seven case subjects and no control subjects (p = 0.005; Fisher exact and permutation tests). Because JMJD1C and RREB1 are involved in chromatin modification, we investigated other histone modification genes. Eighteen case subjects (20%) had rdSNVs in four genes (JMJD1C, RREB1, MINA, KDM7A) all involved in demethylation of histones (H3K9, H3K27). Overall, rdSNVs were enriched in histone modifier genes that activate transcription (Fisher exact p = 0.0004, permutations, p = 0.0003, OR = 5.16); however, rdSNVs in control subjects were not enriched. This implicates histone modification genes as influencing risk for CHD in presence of the deletion.
AB - We performed whole exome sequence (WES) to identify genetic modifiers on 184 individuals with 22q11.2 deletion syndrome (22q11DS), of whom 89 case subjects had severe congenital heart disease (CHD) and 95 control subjects had normal hearts. Three genes including JMJD1C (jumonji domain containing 1C), RREB1 (Ras responsive element binding protein 1), and SEC24C (SEC24 family member C) had rare (MAF < 0.001) predicted deleterious single-nucleotide variations (rdSNVs) in seven case subjects and no control subjects (p = 0.005; Fisher exact and permutation tests). Because JMJD1C and RREB1 are involved in chromatin modification, we investigated other histone modification genes. Eighteen case subjects (20%) had rdSNVs in four genes (JMJD1C, RREB1, MINA, KDM7A) all involved in demethylation of histones (H3K9, H3K27). Overall, rdSNVs were enriched in histone modifier genes that activate transcription (Fisher exact p = 0.0004, permutations, p = 0.0003, OR = 5.16); however, rdSNVs in control subjects were not enriched. This implicates histone modification genes as influencing risk for CHD in presence of the deletion.
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U2 - 10.1016/j.ajhg.2015.10.013
DO - 10.1016/j.ajhg.2015.10.013
M3 - Article
C2 - 26608785
AN - SCOPUS:84952637174
SN - 0002-9297
VL - 97
SP - 869
EP - 877
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -