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

• Published in: American journal of human genetics Vol. 97; no. 6; pp. 869 - 877
• Main Authors: Guo, Tingwei, Chung, Jonathan H., Wang, Tao, McDonald-McGinn, Donna M., Kates, Wendy R., Hawuła, Wanda, Coleman, Karlene, Zackai, Elaine, Emanuel, Beverly S., Morrow, Bernice E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03-12-2015; Cell Press; Elsevier
• Subjects: Cardiovascular disease; Case-Control Studies; Chromatin; Congenital diseases; DiGeorge Syndrome - complications; DiGeorge Syndrome - genetics; DiGeorge Syndrome - pathology; DNA-Binding Proteins - genetics; Exome; Gene Expression Regulation; Genes; Genetics; Heart Defects, Congenital - complications; Heart Defects, Congenital - genetics; Heart Defects, Congenital - pathology; High-Throughput Nucleotide Sequencing; Histones - genetics; Histones - metabolism; Humans; Jumonji Domain-Containing Histone Demethylases - genetics; Molecular Sequence Annotation; Nuclear Proteins - genetics; Oxidoreductases, N-Demethylating - genetics; Phenotype; Polymorphism, Single Nucleotide; Proteins; Risk; Transcription Factors - genetics; Transcription, Genetic; Vesicular Transport Proteins - genetics
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2015.10.013

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.