Histone Modifier Genes Alter Conotruncal Heart Phenotypes in 22q11.2 Deletion Syndrome

Tingwei Guo, Jonathan H. Chung, Tao Wang, Donna M. McDonald-Mcginn, Wendy R. Kates, Wanda Hawuła, Karlene Coleman, Elaine Zackai, Beverly S. Emanuel, Bernice E. Morrow

    Research output: Contribution to journalArticlepeer-review

    34 Scopus citations


    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.

    Original languageEnglish (US)
    Pages (from-to)869-877
    Number of pages9
    JournalAmerican journal of human genetics
    Issue number6
    StatePublished - Dec 3 2015

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)


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