KBG syndrome (KBGS) is characterized by distinctive facial gestalt, short stature and variable clinical findings. With ageing, some features become more recognizable, allowing a differential diagnosis. We aimed to better characterize natural history of KBGS. In the context of a European collaborative study, we collected the largest cohort of KBGS patients (49). A combined array- based Comparative Genomic Hybridization and next generation sequencing (NGS) approach investigated both genomic Copy Number Variants and SNVs. Intellectual disability (ID) (82%) ranged from mild to moderate with severe ID identified in two patients. Epilepsy was present in 26.5%. Short stature was consistent over time, while occipitofrontal circumference (median value: -0.88 SD at birth) normalized over years. Cerebral anomalies, were identified in 56% of patients and thus represented the second most relevant clinical feature reinforcing clinical suspicion in the paediatric age when short stature and vertebral/dental anomalies are vague. Macrodontia, oligodontia and dental agenesis (53%) were almost as frequent as skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age. In 28.5% of individuals, prenatal ultrasound anomalies were reported. Except for three splicing variants, leading to a premature termination, variants were almost all frameshift. Our results, broadening the spectrum of KBGS phenotype progression, provide useful tools to facilitate differential diagnosis and improve clinical management. We suggest to consider a wider range of dental anomalies before excluding diagnosis and to perform a careful odontoiatric/ear-nose-throat (ENT) evaluation in order to look for even submucosal palate cleft given the high percentage of palate abnormalities. NGS approaches, following evidence of antenatal ultrasound anomalies, should include ANKRD11.

Amsterdam UMC location University of Amsterdam Department of Pediatrics Amsterdam 1100 The Netherlands

Area of Clinical and Molecular Genetics Vall d'Hebron University Hospital Barcellona 08035 Spain

Centre for Neurological Diseases West Tallinn Central Hospital Tallinn 10617 Estonia

Clinical Paediatrics Department of Molecular Medicine and Development University of Siena Siena 53100 Italy

Department of Biology and Medical Genetics Charles University 2nd Faculty of Medicine and University Hospital Motol Prague 150 00 Czech Republic

Department of Child Neurology Turku University Hospital Turku 20500 Finland

Department of Clinical and Experimental Medicine University of Pisa Pisa 56122 Italy

Department of Clinical Genetics and Genomics The Cyprus Institute of Neurology and Genetics Nicosia 1683 Cyprus

Department of Clinical Genetics Genetic and Personalized Medicine Clinic Tartu University Hospital Tartu 50406 Estonia

Department of Clinical Genetics PEDEGO Research Unit and Medical Research Center Oulu University of Oulu and Oulu University Hospital Oulu 90014 Finland

Department of Genomics and Clinical Genetics Turku University Hospital Turku 20500 Finland

Department of Molecular and Medical Genetics Tbilisi State Medical University Tbilisi 0162 Georgia

Department of Translational Medicine University of Naples Federico 2 Naples 80125 Italy

Division of Child and Adolescent Neuropsychiatry University of Siena Siena 53100 Italy

Division of Genetic Medicine Lausanne University Hospital and University of Lausanne 1011 Lausanne Switzerland

Genetic Counseling Service Department of Pediatrics Regional Hospital of Bolzano Bolzano 39100 Italy

Genetica Medica Azienda Ospedaliera Universitaria Senese Siena 53100 Italy

Institut de Pathologie et de Génétique; Centre de Génétique Humaine Gosselies 6041 Belgium

Institute for Maternal and Child Health Trieste 34100 Italy

Institute of Clinical Medicine University of Tartu Tartu 50406 Estonia

IRCCS Stella Maris Foundation Department of Developmental Neuroscience Pisa 98125 Italy

IRCCS Stella Maris Foundation Molecular Medicine for Neurodegenerative and Neuromuscular Disease Unit Pisa 98125 Italy

Med Biotech Hub and Competence Centre Department of Medical Biotechnologies University of Siena Siena 53100 Italy

Medical Genetics University of Siena Siena 53100 Italy

National Center of Genetics L 3555 Dudelange Luxembourg

Regional Coordinating Center for Rare Diseases Udine 33100 Italy

William Lennox Neurological Hospital Reference Center for Refractory Epilepsy UCLouvain Ottignies 1340 Belgium

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