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.
Highlights
One additional patient had a microdeletion of 16p24.3 including ANKRD11 identified by array CGH but was excluded from the study
We agree with other authors that while some KBG patients can be recognized by gestalt, others may resemble Cornelia de Lange syndrome (CDLS)
Ansari et al [2014] found that 3/163 CDLS-like patients had ANKRD11 mutations and Busa et al [2015] reported on a French cohort of 20 mutation/deletion cases and commented that the facial features were reminiscent of CDLS
Summary
KBG syndrome (MIM # 148050) [Herrmann et al, 1975] combines short-stature, macrodontia of the permanent central upper incisors, distinctive facial features, learning difficulties, and neurobehavioral problems [Herrmann et al, 1975; Smithson et al, 2000; Skjei et al, 2007; Sirmaci et al, 2011; Youngs et al, 2011]. Other recognized features include seizures, cardiac abnormalities, and hearing loss [Brancati et al, 2006; Youngs et al, 2011; Ockeloen et al, 2015]. Deletions of 16q24 including ANKRD11 were reported to lead to a similar phenotype [Willemsen et al, 2010; Isrie et al, 2012; Sacharow et al, 2012]. Data on older patients is presented, providing insight into the long-term outcome of the condition. Recognition of this diagnosis in young adults has important implications for genetic counselling
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