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Clinical and genetic aspects of KBG syndrome.

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.

SUBMITTER: Low K

PROVIDER: S-EPMC5435101 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Clinical and genetic aspects of KBG syndrome.

Low Karen K Ashraf Tazeen T Canham Natalie N Clayton-Smith Jill J Deshpande Charu C Donaldson Alan A Fisher Richard R Flinter Frances F Foulds Nicola N Fryer Alan A Gibson Kate K Hayes Ian I Hills Alison A Holder Susan S Irving Melita M Joss Shelagh S Kivuva Emma E Lachlan Kathryn K Magee Alex A McConnell Vivienne V McEntagart Meriel M Metcalfe Kay K Montgomery Tara T Newbury-Ecob Ruth R Stewart Fiona F Turnpenny Peter P Vogt Julie J Fitzpatrick David D Williams Maggie M Smithson Sarah S

American journal of medical genetics. Part A 20160926 11

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 al ...[more]

PMID: 27667800

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Project description:BackgroundBardet-Biedl syndrome (BBS) is a rare nonmotile ciliopathy characterized by retinal dystrophy, polydactyly, obesity, genital anomalies, renal dysfunction, and learning difficulties. The objectives were to describe the retinal, oral, and metabolic characteristics relevant to adults with BBS as well as the prevalence of genetic variants.MethodsA cross-sectional study of 30 adults with BBS (15 males, 15 females, mean age 39.8 ± 13.6 years) was recruited from a single centre for rare disorders in Norway. Participants attended a one day hospital visit including medical (blood pressure, body mass index), ophthalmological and oral examinations. Blood samples were collected and genetic analyses were performed.ResultsAge at diagnosis varied from one year to 30 years. The incidence of overweight/obesity, hypertension, kidney disease, and diabetes mellitus was 82%, 67%, 27%, and 23%, respectively. All had retinitis pigmentosa. Prior to the study, 14 participants (47%) had confirmed extinguished electroretinography. Eleven participants were examined with electroretinography during the study period, and all had extinguished electroretinography. 50% perceived light, 23% saw hand motion, and one participant did not perceive light. Oral anomalies were identified in 77% of the participants, including abnormal palates (58%), crowded teeth (50%), and small teeth (60%). A genetic cause was identified in all participants, most commonly in BBS1 (n = 11) and BBS10 (n = 9). Other variants were found in BBS5, BBS7, BBS9, and MKKS. In addition to exon-located variants, a novel deep intronic variant causing mis-splicing was identified in BBS7.ConclusionsA multidisciplinary examination is important for proper management of BBS. The genotype and phenotype of this sample were heterogeneous, including kidney failure, genital anomalies and obesity. Genome sequencing increased the likelihood of identifying the genetic cause. In BBS populations, the patients will benefit from testing or reanalysis, preferably with genome sequencing, including searching for deep intronic variants.

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Clinical and genetic aspects of KBG syndrome.

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Clinical and genetic aspects of KBG syndrome.

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