TY - JOUR
T1 - De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms
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
N1 - Publisher Copyright:
© 2016
PY - 2016/10/6
Y1 - 2016/10/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84991730430&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2016.08.001
DO - 10.1016/j.ajhg.2016.08.001
M3 - Article
C2 - 27616479
AN - SCOPUS:84991730430
SN - 0002-9297
VL - 99
SP - 934
EP - 941
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -