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

Karin Weiss, Paulien A. Terhal, Lior Cohen, Michael Bruccoleri, Melita Irving, Ariel F. Martinez, Jill A. Rosenfeld, Keren Machol, Yaping Yang, Pengfei Liu, Magdalena Walkiewicz, Joke Beuten, Natalia Gomez-Ospina, Katrina Haude, Chin To Fong, Gregory M. Enns, Jonathan A. Bernstein, Judith Fan, Garrett Gotway, Mohammad Ghorbani & 7 others Koen van Gassen, Glen R. Monroe, Gijs van Haaften, Lina Basel-Vanagaite, Xiang Jiao Yang, Philippe M. Campeau, Maximilian Muenke

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)934-941
Number of pages8
JournalAmerican Journal of Human Genetics
Volume99
Issue number4
DOIs
StatePublished - Oct 6 2016

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DNA-Binding Proteins
Intellectual Disability
Chromatin
Adenosine Triphosphate
Mutation
Megalencephaly
Genes
Exome
Histone Deacetylases
Chromatin Assembly and Disassembly
Hypogonadism
Nucleic Acid Databases
Human Development
Hearing Loss
Epigenomics
DNA Repair
Arginine
Cell Cycle
Yeasts
Phenotype

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms. / Weiss, Karin; Terhal, Paulien A.; Cohen, Lior; Bruccoleri, Michael; Irving, Melita; Martinez, Ariel F.; Rosenfeld, Jill A.; Machol, Keren; Yang, Yaping; Liu, Pengfei; Walkiewicz, Magdalena; Beuten, Joke; Gomez-Ospina, Natalia; Haude, Katrina; Fong, Chin To; Enns, Gregory M.; Bernstein, Jonathan A.; Fan, Judith; Gotway, Garrett; Ghorbani, Mohammad; van Gassen, Koen; Monroe, Glen R.; van Haaften, Gijs; Basel-Vanagaite, Lina; Yang, Xiang Jiao; Campeau, Philippe M.; Muenke, Maximilian.

In: American Journal of Human Genetics, Vol. 99, No. 4, 06.10.2016, p. 934-941.

Research output: Contribution to journalArticle

Weiss, K, Terhal, PA, Cohen, L, Bruccoleri, M, Irving, M, Martinez, AF, Rosenfeld, JA, Machol, K, Yang, Y, Liu, P, Walkiewicz, M, Beuten, J, Gomez-Ospina, N, Haude, K, Fong, CT, Enns, GM, Bernstein, JA, Fan, J, Gotway, G, Ghorbani, M, van Gassen, K, Monroe, GR, van Haaften, G, Basel-Vanagaite, L, Yang, XJ, Campeau, PM & Muenke, M 2016, 'De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms', American Journal of Human Genetics, vol. 99, no. 4, pp. 934-941. https://doi.org/10.1016/j.ajhg.2016.08.001
Weiss, Karin ; Terhal, Paulien A. ; Cohen, Lior ; Bruccoleri, Michael ; Irving, Melita ; Martinez, Ariel F. ; Rosenfeld, Jill A. ; Machol, Keren ; Yang, Yaping ; Liu, Pengfei ; Walkiewicz, Magdalena ; Beuten, Joke ; Gomez-Ospina, Natalia ; Haude, Katrina ; Fong, Chin To ; Enns, Gregory M. ; Bernstein, Jonathan A. ; Fan, Judith ; Gotway, Garrett ; Ghorbani, Mohammad ; van Gassen, Koen ; Monroe, Glen R. ; van Haaften, Gijs ; Basel-Vanagaite, Lina ; Yang, Xiang Jiao ; Campeau, Philippe M. ; Muenke, Maximilian. / De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms. In: American Journal of Human Genetics. 2016 ; Vol. 99, No. 4. pp. 934-941.
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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.",
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AU - Weiss, Karin

AU - Terhal, Paulien A.

AU - Cohen, Lior

AU - Bruccoleri, Michael

AU - Irving, Melita

AU - Martinez, Ariel F.

AU - Rosenfeld, Jill A.

AU - Machol, Keren

AU - Yang, Yaping

AU - Liu, Pengfei

AU - Walkiewicz, Magdalena

AU - Beuten, Joke

AU - Gomez-Ospina, Natalia

AU - Haude, Katrina

AU - Fong, Chin To

AU - Enns, Gregory M.

AU - Bernstein, Jonathan A.

AU - Fan, Judith

AU - Gotway, Garrett

AU - Ghorbani, Mohammad

AU - van Gassen, Koen

AU - Monroe, Glen R.

AU - van Haaften, Gijs

AU - Basel-Vanagaite, Lina

AU - Yang, Xiang Jiao

AU - Campeau, Philippe M.

AU - Muenke, Maximilian

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