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Am J Med Genet A. 2016 Nov;170(11):2835-2846. doi: 10.1002/ajmg.a.37842. Epub 2016 Sep 26.

Clinical and genetic aspects of KBG syndrome.

Author information

1
University Hospitals Bristol NHS Trust/University of Bristol, Bristol, United Kingdom. Karen.low1@nhs.net.
2
Guy's and St Thomas' NHS Trust, London, United Kingdom.
3
North West Thames Regional Genetics Service, Harrow, London, United Kingdom.
4
Manchester Centre For Genomic Medicine, St Mary's Hospital Manchester, United Kingdom.
5
Institute of Human Development, University of Manchester, Manchester, United Kingdom.
6
University Hospitals Bristol NHS Trust/University of Bristol, Bristol, United Kingdom.
7
Teesside Genetics Unit, The James Cook University Hospital, Middlesbrough, United Kingdom.
8
Wessex Clinical Genetics Service, Southampton, United Kingdom.
9
Liverpool Women's NHS Trust, Liverpool, United Kingdom.
10
Genetic Health Service NZ, Christchurch Hospital, Christchurch, New Zealand.
11
Genetic Health Service NZ, Auckland Hospital, Auckland, New Zealand.
12
Bristol Genetics Laboratory, North Bristol NHS Trust, Bristol, United Kingdom.
13
West of Scotland Department of Clinical Genetics, Glasgow, United Kingdom.
14
Royal Devon and Exeter Hospital, Exeter, United Kingdom.
15
Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Ireland.
16
South West Thames Clinical Genetics Service, St Georges Hospital, London, United Kingdom.
17
Northern Genetics Service, Newcastle Upon Tyne, United Kingdom.
18
West Midlands Regional Genetics Service, Birmingham, United Kingdom.
19
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
20
Wellcome Trust Sanger Institute, Cambridgeshire, United Kingdom.

Abstract

KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. We describe 32 KBG patients aged 2-47 years from 27 families ascertained via two pathways: targeted ANKRD11 sequencing (TS) in a group who had a clinical diagnosis of KBG and whole exome sequencing (ES) in a second group in whom the diagnosis was unknown. Speech delay and learning difficulties were almost universal and variable behavioral problems frequent. Macrodontia of permanent upper central incisors was seen in 85%. Other clinical features included short stature, conductive hearing loss, recurrent middle ear infection, palatal abnormalities, and feeding difficulties. We recognized a new feature of a wide anterior fontanelle with delayed closure in 22%. The subtle facial features of KBG syndrome were recognizable in half the patients. We identified 20 ANKRD11 mutations (18 novel: all truncating) confirmed by Sanger sequencing in 32 patients. Comparison of the two ascertainment groups demonstrated that facial/other typical features were more subtle in the ES group. There were no conclusive phenotype-genotype correlations. Our findings suggest that mutation of ANKRD11 is a common Mendelian cause of developmental delay. Affected patients may not show the characteristic KBG phenotype and the diagnosis is therefore easily missed. We propose updated diagnostic criteria/clinical recommendations for KBG syndrome and suggest that inclusion of ANKRD11 will increase the utility of gene panels designed to investigate developmental delay. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

KEYWORDS:

ANKRD11; KBG syndrome; macrodontia

PMID:
27667800
PMCID:
PMC5435101
DOI:
10.1002/ajmg.a.37842
[Indexed for MEDLINE]
Free PMC Article

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