Am J Hum Genet. 2016 Oct 6;99(4):934-941. doi: 10.1016/j.ajhg.2016.08.001. Epub 2016 Sep 8.

De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms.

Weiss K¹, Terhal PA², Cohen L³, Bruccoleri M⁴, Irving M⁵, Martinez AF¹, Rosenfeld JA⁶, Machol K⁶, Yang Y⁶, Liu P⁶, Walkiewicz M⁶, Beuten J⁶, Gomez-Ospina N⁷, Haude K⁸, Fong CT⁸, Enns GM⁷, Bernstein JA⁷, Fan J⁹, Gotway G⁹, Ghorbani M⁴; DDD Study, van Gassen K², Monroe GR¹⁰, van Haaften G¹⁰, Basel-Vanagaite L¹¹, Yang XJ⁴, Campeau PM¹², Muenke M¹³.

Author information

1: Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
2: Department of Genetics, Utrecht University Medical Center, Utrecht 3584 CX, the Netherlands.
3: Pediatric Genetics, Schneider Children Medical Center of Israel, Petah Tikva 49202, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
4: Rosalind and Morris Goodman Cancer Research Center, McGill University, and Department of Medicine, McGill University Health Center, Montreal, QC H3G 2M1, Canada.
5: Department of Clinical Genetics, Guy's Hospital, London SE1 9RT, UK.
6: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
7: Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
8: Department of Pediatric Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
9: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
10: Department of Genetics, Utrecht University Medical Center, Utrecht 3584 CX, the Netherlands; Center for Molecular Medicine, Utrecht University Medical Center, Utrecht 3584 CX, the Netherlands.
11: Pediatric Genetics, Schneider Children Medical Center of Israel, Petah Tikva 49202, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel; Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 49100, Israel.
12: Department of Pediatrics, Sainte-Justine Hospital, University of Montreal, Montreal, QC H3T 1C4, Canada. Electronic address: p.campeau@umontreal.ca.
13: Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address: mmuenke@nhgri.nih.gov.

Abstract

Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATP-dependent chromatin remodeler involved in epigenetic regulation of gene transcription, DNA repair, and cell cycle progression. Also known as Mi2β, CHD4 is an integral subunit of a well-characterized histone deacetylase complex. Here we report five individuals with de novo missense substitutions in CHD4 identified through whole-exome sequencing and web-based gene matching. These individuals have overlapping phenotypes including developmental delay, intellectual disability, hearing loss, macrocephaly, distinct facial dysmorphisms, palatal abnormalities, ventriculomegaly, and hypogonadism as well as additional findings such as bone fusions. The variants, c.3380G>A (p.Arg1127Gln), c.3443G>T (p.Trp1148Leu), c.3518G>T (p.Arg1173Leu), and c.3008G>A, (p.Gly1003Asp) (GenBank: NM_001273.3), affect evolutionarily highly conserved residues and are predicted to be deleterious. Previous studies in yeast showed the equivalent Arg1127 and Trp1148 residues to be crucial for SNF2 function. Furthermore, mutations in the same positions were reported in malignant tumors, and a de novo missense substitution in an equivalent arginine residue in the C-terminal helicase domain of SMARCA4 is associated with Coffin Siris syndrome. Cell-based studies of the p.Arg1127Gln and p.Arg1173Leu mutants demonstrate normal localization to the nucleus and HDAC1 interaction. Based on these findings, the mutations potentially alter the complex activity but not its formation. This report provides evidence for the role of CHD4 in human development and expands an increasingly recognized group of Mendelian disorders involving chromatin remodeling and modification.