title: Histone Modifier Genes Alter Conotruncal Heart Phenotypes in 22q11.2 Deletion Syndrome.
abstract: 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.
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA.
authors.forename: Tingwei
authors.initials: T
authors.lastname: Guo
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Chung
authors.affiliation: Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Division of Human Genetics, The Children's Hospital of Philadelphia, and Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: McDonald-McGinn
authors.affiliation: Department of Psychiatry and Behavioral Sciences, and Program in Neuroscience, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: Wendy R
authors.initials: WR
authors.lastname: Kates
authors.affiliation: Department of Genetics, Polish Mother's Memorial Hospital - Research Institute, Łódź 93-338, Poland.
authors.forename: Wanda
authors.initials: W
authors.lastname: Hawuła
authors.affiliation: Marcus Autism Center, Children's Healthcare of Atlanta, Atlanta, GA 30329, USA.
authors.forename: Karlene
authors.initials: K
authors.lastname: Coleman
authors.affiliation: Division of Human Genetics, The Children's Hospital of Philadelphia, and Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Zackai
authors.affiliation: Division of Human Genetics, The Children's Hospital of Philadelphia, and Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Emanuel
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA. Electronic address: bernice.morrow@einstein.yu.edu.
authors.forename: Bernice E
authors.initials: BE
authors.lastname: Morrow
mesh_terms: D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D004062:DiGeorge Syndrome / Q000150:complications / Q000235:genetics* / Q000473:pathology; D049308:Dioxygenases; D059472:Exome; D005786:Gene Expression Regulation; D006330:Heart Defects, Congenital / Q000150:complications / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D056466:Histone Demethylases; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics*; D058977:Molecular Sequence Annotation; D009687:Nuclear Proteins / Q000235:genetics*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D033921:Vesicular Transport Proteins / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; C101743:RREB1 protein, human; C530640:SEC24C protein, human; D014157:Transcription Factors; D033921:Vesicular Transport Proteins; D049308:Dioxygenases; D056466:Histone Demethylases; C520448:JMJD1C protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; C548973:KDM7A protein, human; C466777:RIOX2 protein, human; D010089:Oxidoreductases, N-Demethylating