CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

被引：85

作者：

Blok, Lot Snijders ^{[1
,2
,3
]}

Rousseau, Justine ^{[4
]}

Twist, Joanna ^{[5
]}

Ehresmann, Sophie ^{[4
]}

Takaku, Motoki ^{[5
]}

Venselaar, Hanka ^{[6
]}

Rodan, Lance H. ^{[7
]}

Nowak, Catherine B. ^{[7
]}

Douglas, Jessica ^{[7
]}

Swoboda, Kathryn J. ^{[8
,9
]}

Steeves, Marcie A. ^{[10
]}

Sahai, Inderneel ^{[10
]}

Stumpel, Connie T. R. M. ^{[11
,12
]}

Stegmann, Alexander P. A. ^{[11
,12
]}

Wheeler, Patricia ^{[13
]}

Willing, Marcia ^{[14
]}

Fiala, Elise ^{[14
]}

Kochhar, Aaina ^{[15
]}

Gibson, William T. ^{[16
,17
]}

Cohen, Ana S. A. ^{[16
,17
]}

Agbahovbe, Ruky ^{[16
,17
]}

Innes, A. Micheil ^{[18
,19
]}

Au, P. Y. Billie ^{[18
,19
]}

Rankin, Julia ^{[20
]}

Anderson, Ilse J. ^{[21
]}

Skinner, Steven A. ^{[22
]}

Louie, Raymond J. ^{[22
]}

Warren, Hannah E. ^{[22
]}

Afenjar, Alexandra ^{[23
,24
]}

Keren, Boris ^{[25
,26
]}

Nava, Caroline ^{[25
,26
,27
]}

Buratti, Julien ^{[25
]}

Isapof, Arnaud ^{[28
,29
]}

Rodriguez, Diana ^{[28
,30
]}

Lewandowski, Raymond ^{[31
]}

Propst, Jennifer ^{[31
]}

van Essen, Ton ^{[32
]}

Choi, Murim ^{[33
]}

Lee, Sangmoon ^{[33
]}

Chae, Jong H. ^{[34
]}

Price, Susan ^{[35
]}

Schnur, Rhonda E. ^{[36
]}

Douglas, Ganka ^{[36
]}

Wentzensen, Ingrid M. ^{[36
]}

Zweier, Christiane ^{[37
]}

Reis, Andre ^{[37
]}

Bialer, Martin G. ^{[38
]}

Moore, Christine ^{[38
]}

Koopmans, Marije ^{[39
]}

Brilstra, Eva H. ^{[39
]}

机构：

[1] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, NL-6500 HB Nijmegen, Netherlands

[2] Max Planck Inst Psycholinguist, Language & Genet Dept, NL-6500 AH Nijmegen, Netherlands

[3] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6500 HE Nijmegen, Netherlands

[4] CHU St Justine Res Ctr, Montreal, PQ H3T 1C5, Canada

[5] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA

[6] Radboud Univ Nijmegen, Ctr Mol & Biomol Informat, Radboud Inst Mol Life Sci, Med Ctr, NL-6500 HB Nijmegen, Netherlands

[7] Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA

[8] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[9] Harvard Med Sch, Boston, MA 02114 USA

[10] Massachusetts Gen Hosp, Dept Med Genet, Boston, MA 02114 USA

[11] Maastricht Univ, Dept Clin Genet, Med Ctr, NL-6202 AZ Maastricht, Netherlands

[12] Maastricht Univ, GROW Sch Oncol & Dev Biol, Med Ctr, NL-6202 AZ Maastricht, Netherlands

[13] Nemours Childrens Clin, Orlando, FL 32827 USA

[14] Washington Univ, Dept Pediat, Div Genet & Genom Med, Sch Med, St Louis, MO 63110 USA

[15] Valley Childrens Hosp, Madera, CA 93636 USA

[16] British Columbia Childrens Hosp, Res Inst, Vancouver, BC V5Z 4H4, Canada

[17] Univ British Columbia, Dept Med Genet, Vancouver, BC V6H 3N1, Canada

[18] Univ Calgary, Dept Med Genet, Cumming Sch Med, Res Inst, Calgary, AB T2N 4N1, Canada

[19] Univ Calgary, Alberta Childrens Hosp, Cumming Sch Med, Res Inst, Calgary, AB T2N 4N1, Canada

[20] Royal Devon & Exeter NHS Fdn Trust Heavitree, Dept Clin Genet, Exeter EX2 5DW, Devon, England

[21] Univ Tennessee, Dept Med, Div Genet, Med Ctr, Knoxville, TN 37920 USA

[22] Greenwood Genet Ctr, Greenwood, SC 29646 USA

[23] UPMC Univ Paris, GRC ConCer LD, Sorbonne Univ, Dept Med Genet, F-75012 Paris, France

[24] Armand Trousseau Hosp, AP HP, GHUEP, Ctr Reference Malformat & Malad Congenitales Cerv, F-75012 Paris, France

[25] Hop La Pitie Salpetriere, AP HP, Dept Genet, F-75013 Paris, France

[26] UPMC, Grp Rech Clin GRC Deficience Intellectuelle & Aut, F-75005 Paris, France

[27] UPMC Univ Paris 06, UMR S 1127, Sorbonne Univ, INSERM,CNRS UMR 7225,U1127,ICM,Inst Cerveau Moell, F-75013 Paris, France

[28] UPMC Univ Paris 06, Sorbonne Univ, Dept Child Neurol, GRC ConCer LD, F-75012 Paris, France

[29] Armand Trousseau Hosp, AP HP, GHUEP, FILNEMUS,Reference Ctr Neuromuscular Dis Nord Est, F-75012 Paris, France

[30] Armand Trousseau Hosp, AP HP, Natl Reference Ctr Neurogenet Disorders, GHUEP,INSERM U1141, F-75012 Paris, France

[31] Virginia Commonwealth Univ Hlth Syst, Clin Genet Div, Richmond, VA 23298 USA

[32] Univ Med Ctr Groningen, Clin Genet Dept, NL-9700 RB Groningen, Netherlands

[33] Seoul Natl Univ, Dept Biomed Sci, Coll Med, Seoul 08826, South Korea

[34] Seoul Natl Univ, Childrens Hosp, Dept Pediat, Coll Med, Seoul 08826, South Korea

[35] Oxford Univ Hosp NHS Fdn Trust, Oxford OX3 7HE, England

[36] GeneDx, Gaithersburg, MD 20877 USA

[37] Friedrich Alexander Univ Erlangen Nurnberg, Inst Human Genet, D-91054 Erlangen, Germany

[38] Northwell Hlth, Div Med Genet & Genom, Great Neck, NY 11021 USA

[39] Univ Utrecht, Univ Med Ctr Utrecht, Dept Genet, NL-3508 AB Utrecht, Netherlands

[40] St Michaels Hosp, Univ Hosp Bristol, Dept Clin Genet, Bristol BS2 8EG, Avon, England

[41] Paracelsus Med Univ, Univ Childrens Hosp, Dept Clin Genet, A-5020 Salzburg, Austria

[42] Salzburger Landeskliniken & Paracelsus Med Univ, Dept Pediat, A-5020 Salzburg, Austria

[43] Tech Univ Munich, Inst Human Genet, D-81675 Munich, Germany

[44] Helmholtz Zentrum Munchen, Inst Human Genet, D-85764 Neuherberg, Germany

[45] Augustana Coll, Commun Sci & Disorders, Rock Isl, IL 61201 USA

[46] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA

[47] Univ Med Ctr Hamburg Eppendorf, Inst Human Genet, D-20246 Hamburg, Germany

[48] Waseda Univ, Tokyo 1698050, Japan

[49] Univ Bourgogne Franche Comte, Equipe Genet Anomalies Dev, F-21070 Dijon, France

[50] CHU Dijon, Ctr Genet, Hop Enfants, FHU TRANSLAD, F-21079 Dijon, France

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

英国惠康基金; 加拿大健康研究院;

关键词：

DE-NOVO MUTATIONS; INTELLECTUAL DISABILITY; CHROMATIN; COMPLEX; EXOME; DEACETYLASE; FAMILY; GENE; NURD; DISORDERS;

D O I：

10.1038/s41467-018-06014-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.

引用

页数：12

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