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Clinical and genetic aspects of KBG syndrome

Clinical and genetic aspects of KBG syndrome
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
1552-4825
2835-2846
Low, Karen
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Ashraf, Tazeen
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Canham, Natalie
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Clayton-Smith, Jill
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Deshpande, Charu
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Donaldson, Alan
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Fisher, Richard
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Flinter, Frances
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Foulds, Nicola
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Fryer, Alan
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Gibson, Kate
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Hayes, Ian
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Hills, Alison
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Holder, Susan
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Irving, Melita
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Joss, Shelagh
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Kivuva, Emma
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Lachlan, Kathryn
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Magee, Alex
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McConnell, Vivienne
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McEntagart, Meriel
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Metcalfe, Kay
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Montgomery, Tara
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Newbury-Ecob, Ruth
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Stewart, Fiona
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Turnpenny, Peter
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Vogt, Julie
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Fitzpatrick, David
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Williams, Maggie
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Smithson, Sarah
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Low, Karen
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Ashraf, Tazeen
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Canham, Natalie
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Clayton-Smith, Jill
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Deshpande, Charu
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Donaldson, Alan
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Fisher, Richard
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Flinter, Frances
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Foulds, Nicola
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Fryer, Alan
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Gibson, Kate
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Hayes, Ian
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Hills, Alison
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Holder, Susan
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Irving, Melita
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Joss, Shelagh
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Kivuva, Emma
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Lachlan, Kathryn
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Magee, Alex
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McConnell, Vivienne
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McEntagart, Meriel
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Metcalfe, Kay
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Montgomery, Tara
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Newbury-Ecob, Ruth
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Stewart, Fiona
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Turnpenny, Peter
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Vogt, Julie
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Fitzpatrick, David
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Williams, Maggie
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Smithson, Sarah
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Low, Karen, Ashraf, Tazeen, Canham, Natalie, Clayton-Smith, Jill, Deshpande, Charu, Donaldson, Alan, Fisher, Richard, Flinter, Frances, Foulds, Nicola, Fryer, Alan, Gibson, Kate, Hayes, Ian, Hills, Alison, Holder, Susan, Irving, Melita, Joss, Shelagh, Kivuva, Emma, Lachlan, Kathryn, Magee, Alex, McConnell, Vivienne, McEntagart, Meriel, Metcalfe, Kay, Montgomery, Tara, Newbury-Ecob, Ruth, Stewart, Fiona, Turnpenny, Peter, Vogt, Julie, Fitzpatrick, David, Williams, Maggie and Smithson, Sarah (2016) Clinical and genetic aspects of KBG syndrome. American Journal of Medical Genetics part A, 170 (11), 2835-2846. (doi:10.1002/ajmg.a.37842).

Record type: Article

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

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Accepted/In Press date: 17 June 2016
e-pub ahead of print date: 26 September 2016
Published date: November 2016
Organisations: Human Development & Health

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Local EPrints ID: 402670
URI: http://eprints.soton.ac.uk/id/eprint/402670
ISSN: 1552-4825
PURE UUID: 442724e8-0bcf-404a-91f4-5a053f83009b

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Date deposited: 14 Nov 2016 12:56
Last modified: 06 Oct 2020 17:16

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Contributors

Author: Karen Low
Author: Tazeen Ashraf
Author: Natalie Canham
Author: Jill Clayton-Smith
Author: Charu Deshpande
Author: Alan Donaldson
Author: Richard Fisher
Author: Frances Flinter
Author: Nicola Foulds
Author: Alan Fryer
Author: Kate Gibson
Author: Ian Hayes
Author: Alison Hills
Author: Susan Holder
Author: Melita Irving
Author: Shelagh Joss
Author: Emma Kivuva
Author: Kathryn Lachlan
Author: Alex Magee
Author: Vivienne McConnell
Author: Meriel McEntagart
Author: Kay Metcalfe
Author: Tara Montgomery
Author: Ruth Newbury-Ecob
Author: Fiona Stewart
Author: Peter Turnpenny
Author: Julie Vogt
Author: David Fitzpatrick
Author: Maggie Williams
Author: Sarah Smithson

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