Clinical and genetic aspects of KBG syndrome.
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.
University Hospitals Bristol NHS Trust/University of Bristol, Bristol, United Kingdom. Karen.low1@nhs.net.
Karen
K
Low
Guy's and St Thomas' NHS Trust, London, United Kingdom.
Tazeen
T
Ashraf
North West Thames Regional Genetics Service, Harrow, London, United Kingdom.
Natalie
N
Canham
Manchester Centre For Genomic Medicine, St Mary's Hospital Manchester, United Kingdom.|Institute of Human Development, University of Manchester, Manchester, United Kingdom.
Jill
J
Clayton-Smith
Guy's and St Thomas' NHS Trust, London, United Kingdom.
Charu
C
Deshpande
University Hospitals Bristol NHS Trust/University of Bristol, Bristol, United Kingdom.
Alan
A
Donaldson
Teesside Genetics Unit, The James Cook University Hospital, Middlesbrough, United Kingdom.
Richard
R
Fisher
Guy's and St Thomas' NHS Trust, London, United Kingdom.
Frances
F
Flinter
Wessex Clinical Genetics Service, Southampton, United Kingdom.
Nicola
N
Foulds
Liverpool Women's NHS Trust, Liverpool, United Kingdom.
Alan
A
Fryer
Genetic Health Service NZ, Christchurch Hospital, Christchurch, New Zealand.
Kate
K
Gibson
Genetic Health Service NZ, Auckland Hospital, Auckland, New Zealand.
Ian
I
Hayes
Bristol Genetics Laboratory, North Bristol NHS Trust, Bristol, United Kingdom.
Alison
A
Hills
North West Thames Regional Genetics Service, Harrow, London, United Kingdom.
Susan
S
Holder
Guy's and St Thomas' NHS Trust, London, United Kingdom.
Melita
M
Irving
West of Scotland Department of Clinical Genetics, Glasgow, United Kingdom.
Shelagh
S
Joss
Royal Devon and Exeter Hospital, Exeter, United Kingdom.
Emma
E
Kivuva
Wessex Clinical Genetics Service, Southampton, United Kingdom.
Kathryn
K
Lachlan
Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Ireland.
Alex
A
Magee
Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Ireland.
Vivienne
V
McConnell
South West Thames Clinical Genetics Service, St Georges Hospital, London, United Kingdom.
Meriel
M
McEntagart
Manchester Centre For Genomic Medicine, St Mary's Hospital Manchester, United Kingdom.
Kay
K
Metcalfe
Northern Genetics Service, Newcastle Upon Tyne, United Kingdom.
Tara
T
Montgomery
University Hospitals Bristol NHS Trust/University of Bristol, Bristol, United Kingdom.
Ruth
R
Newbury-Ecob
Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Ireland.
Fiona
F
Stewart
Royal Devon and Exeter Hospital, Exeter, United Kingdom.
Peter
P
Turnpenny
West Midlands Regional Genetics Service, Birmingham, United Kingdom.
Julie
J
Vogt
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
David
D
Fitzpatrick
Bristol Genetics Laboratory, North Bristol NHS Trust, Bristol, United Kingdom.
Maggie
M
Williams
Wellcome Trust Sanger Institute, Cambridgeshire, United Kingdom.
University Hospitals Bristol NHS Trust/University of Bristol, Bristol, United Kingdom.
Sarah
S
Smithson
D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics*; D001848:Bone Diseases, Developmental / Q000175:diagnosis* / Q000235:genetics*; D002872:Chromosome Deletion; D002885:Chromosomes, Human, Pair 16; D055028:Comparative Genomic Hybridization; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics; D014071:Tooth Abnormalities / Q000175:diagnosis* / Q000235:genetics*
C492515:ANKRD11 protein, human; D012097:Repressor Proteins
ANKRD11; KBG syndrome; macrodontia
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