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Clin Genet. 2019 Jul;96(1):72-84. doi: 10.1111/cge.13554. Epub 2019 May 14.

The clinical presentation caused by truncating CHD8 variants.

Author information

1
Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
2
Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK.
3
Academic Department of Medical Genetics, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge, Cambridge, UK.
4
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
5
Northern Ireland Regional Genetics Centre, Belfast Health and Social Care Trust, Belfast City Hospital, Belfast, UK.
6
West of Scotland Regional Genetics Service, NHS Greater Glasgow and Clyde, Institute of Medical Genetics, Yorkhill Hospital, Glasgow, UK.
7
KwaZulu-Natal Research and Innovation Sequencing Platform (KRISP), University of KwaZulu-Natal, Durban, South Africa.
8
Department of Clinical Genetics, Temple Street Children's Hospital, Dublin, Ireland.
9
North West Thames Regional Genetics Service, London, UK.
10
Wellcome Sanger Institute, Cambridge, UK.

Abstract

Variants in the chromodomain helicase DNA-binding protein 8 (CHD8) have been associated with intellectual disability (ID), autism spectrum disorders (ASDs) and overgrowth and CHD8 is one of the causative genes for OGID (overgrowth and ID). We investigated 25 individuals with CHD8 protein truncating variants (PTVs), including 10 previously unreported patients and found a male to female ratio of 2.7:1 (19:7) and a pattern of common features: macrocephaly (62.5%), tall stature (47%), developmental delay and/or intellectual disability (81%), ASDs (84%), sleep difficulties (50%), gastrointestinal problems (40%), and distinct facial features. Most of the individuals in this cohort had moderate-to-severe ID, some had regression of speech (37%), seizures (27%) and hypotonia (27%) and two individuals were non-ambulant. Our study shows that haploinsufficiency of CHD8 is associated with a distinctive OGID syndrome with pronounced autistic traits and supports a sex-dependent penetrance of CHD8 PTVs in humans.

KEYWORDS:

CHD8; OGID; autism; macrocephaly; overgrowth

PMID:
31001818
DOI:
10.1111/cge.13554

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