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Eur J Hum Genet. 2015 Sep;23(9):1176-85. doi: 10.1038/ejhg.2014.253. Epub 2014 Nov 26.

Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations.

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Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
1] Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands [2] South Australian Clinical Genetics Service, SA Pathology at Women's and Children's Hospital, North Adelaide, SA, Australia.
Department of Paediatric Neurology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
Center for Human and Clinical Genetics, Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
1] Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK [2] Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, MAHSC, Manchester, UK.
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
1] Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden [2] Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
Department of Oral and Maxillofacial Surgery, Radboud University Medical Center, Nijmegen, The Netherlands.
Centre for Special Dental Care, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, The Netherlands.


Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.

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