CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems.
BACKGROUND
The chromodomain helicase DNA binding domain (CHD) proteins modulate gene expression via their ability to remodel chromatin structure and influence histone acetylation. Recent studies have shown that CHD2 protein plays a critical role in embryonic development, tumor suppression and survival. Like other genes encoding members of the CHD family, pathogenic mutations in the CHD2 gene are expected to be implicated in human disease. In fact, there is emerging evidence suggesting that CHD2 might contribute to a broad spectrum of neurodevelopmental disorders. Despite growing evidence, a description of the full phenotypic spectrum of this condition is lacking.


METHODS
We conducted a multicentre study to identify and characterise the clinical features associated with haploinsufficiency of CHD2. Patients with deletions of this gene were identified from among broadly ascertained clinical cohorts undergoing genomic microarray analysis for developmental delay, congenital anomalies and/or autism spectrum disorder.


RESULTS
Detailed clinical assessments by clinical geneticists showed recurrent clinical symptoms, including developmental delay, intellectual disability, epilepsy, behavioural problems and autism-like features without characteristic facial gestalt or brain malformations observed on magnetic resonance imaging scans. Parental analysis showed that the deletions affecting CHD2 were de novo in all four patients, and analysis of high-resolution microarray data derived from 26,826 unaffected controls showed no deletions of this gene.


CONCLUSIONS
The results of this study, in addition to our review of the literature, support a causative role of CHD2 haploinsufficiency in developmental delay, intellectual disability, epilepsy and behavioural problems, with phenotypic variability between individuals.
Division of Medical Genetics, Department of Pediatrics, Centre Hospitalier Universitaire de Sherbrooke, 3001, 12E Avenue Nord, Sherbrooke, QC J1H 5N4, Canada.
Sébastien
S
Chénier
Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, 555 University Ave, Toronto, ON M5G 1X8, Canada.
Grace
G
Yoon
Department of Medical Genetics, Alberta Children's Hospital Research Institute, University of Calgary, 2888 Shaganappi Trail NW, Calgary, AB T3B 6A8, Canada.
Bob
B
Argiropoulos
Department of Medical Genetics, Alberta Children's Hospital Research Institute, University of Calgary, 2888 Shaganappi Trail NW, Calgary, AB T3B 6A8, Canada.
Julie
J
Lauzon
Division of Medical Genetics, Department of Pediatrics, Centre Hospitalier Universitaire de Québec, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada.
Rachel
R
Laframboise
Cytogenetics Department, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK.
Joo Wook
JW
Ahn
Cytogenetics Department, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK.
Caroline Mackie
CM
Ogilvie
Department of Molecular Genetics and McLaughlin Centre, The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, 686 Bay Street, Toronto, ON M5G 0A4, Canada.
Anath C
AC
Lionel
Department of Molecular Genetics and McLaughlin Centre, The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, 686 Bay Street, Toronto, ON M5G 0A4, Canada.
Christian R
CR
Marshall
Division of Anatomic Pathology and Cytopathology, Cytogenetics Laboratory, Calgary Laboratory Service and Alberta Children's Hospital, 2888 Shaganappi Trail NW, Calgary, AB T3B 6A8, Canada.
Andrea K
AK
Vaags
Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, 555 University Ave, Toronto, ON M5G 1X8, Canada.
Bita
B
Hashemi
Division of Medical Genetics, Department of Pediatrics, Centre Hospitalier Universitaire de Québec, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada.
Karine
K
Boisvert
Division of Medical Genetics, Department of Pediatrics, Centre Hospitalier Universitaire de Sainte-Justine, Université de Montréal, 3175, Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada.
Géraldine
G
Mathonnet
Division of Medical Genetics, Department of Pediatrics, Centre Hospitalier Universitaire de Sainte-Justine, Université de Montréal, 3175, Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada.
Frédérique
F
Tihy
Department of Clinical Genetics, Lakeridge Health Oshawa, 1 Hospital Court, Oshawa, ON L1G 2B9, Canada.
Joyce
J
So
Department of Molecular Genetics and McLaughlin Centre, The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, 686 Bay Street, Toronto, ON M5G 0A4, Canada.
Stephen W
SW
Scherer
Division of Medical Genetics, Department of Pediatrics, Centre Hospitalier Universitaire de Sainte-Justine, Université de Montréal, 3175, Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada.
Emmanuelle
E
Lemyre
Department of Paediatric Laboratory Medicine, The Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
Dimitri J
DJ
Stavropoulos
Autism spectrum disorder; CHD2; Developmental delay; Epilepsy; Learning disability