University of Oulu

Lorenzo Loberti, Lucia Pia Bruno, Stefania Granata, Gabriella Doddato, Sara Resciniti, Francesca Fava, Michele Carullo, Elisa Rahikkala, Guillaume Jouret, Leonie A Menke, Damien Lederer, Pascal Vrielynck, Lukáš Ryba, Nicola Brunetti-Pierri, Amaia Lasa-Aranzasti, Anna Maria Cueto-González, Laura Trujillano, Irene Valenzuela, Eduardo F Tizzano, Alessandro Mauro Spinelli, Irene Bruno, Aurora Currò, Franco Stanzial, Francesco Benedicenti, Diego Lopergolo, Filippo Maria Santorelli, Constantia Aristidou, George A Tanteles, Isabelle Maystadt, Tinatin Tkemaladze, Tiia Reimand, Helen Lokke, Katrin Õunap, Maria K Haanpää, Andrea Holubová, Veronika Zoubková, Martin Schwarz, Riina Žordania, Kai Muru, Laura Roht, Annika Tihveräinen, Rita Teek, Ulvi Thomson, Isis Atallah, Andrea Superti-Furga, Sabrina Buoni, Roberto Canitano, Valeria Scandurra, Annalisa Rossetti, Salvatore Grosso, Roberta Battini, Margherita Baldassarri, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Mirella Bruttini, Francesca Mari, Francesca Ariani, Alessandra Renieri, Anna Maria Pinto, Natural history of KBG syndrome in a large European cohort, Human Molecular Genetics, 2022;, ddac167,

Natural history of KBG syndrome in a large European cohort

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Author: Loberti, Lorenzo1,2; Bruno, Lucia Pia1,2; Granata, Stefania1,2;
Organizations: 1Medical Genetics, University of Siena, Siena 53100, Italy
2Med Biotech Hub and Competence Centre, Department of Medical Biotechnologies, University of Siena, Siena 53100, Italy
3Department of Clinical Genetics, PEDEGO Research Unit, and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu 90014, Finland
4National Center of Genetics (NCG), Laboratoire national de santé (LNS), L-3555 Dudelange, Luxembourg
5Amsterdam UMC location University of Amsterdam, Department of Pediatrics, Amsterdam 1100, The Netherlands
6Institut de Pathologie et de Génétique; Centre de Génétique Humaine, Gosselies 6041, Belgium
7William Lennox Neurological Hospital, Reference Center for Refractory Epilepsy UCLouvain, Ottignies 1340, Belgium
8Department of Biology and Medical Genetics, Charles University – 2 Faculty of Medicine and University Hospital Motol, Prague 150 00, Czech Republic
9Department of Translational Medicine, University of Naples "Federico II", Naples 80125, Italy
10Area of Clinical and Molecular Genetics, Vall d’Hebron University Hospital, Barcellona 08035, Spain
11Regional Coordinating Center for Rare Diseases, Udine 33100, Italy
12Institute for Maternal and Child Health, Trieste 34100, Italy
13Genetic Counseling Service, Department of Pediatrics, Regional Hospital of Bolzano, Bolzano 39100, Italy
14IRCCS Stella Maris Foundation, Molecular Medicine for Neurodegenerative and Neuromuscular Disease Unit, Pisa 98125, Italy
15Department of Clinical Genetics and Genomics, The Cyprus Institute of Neurology & Genetics, Nicosia 1683, Cyprus
16Department of Molecular and Medical Genetics, Tbilisi State Medical University, Tbilisi 0162, Georgia
17Department of Clinical Genetics, Genetic and Personalized Medicine Clinic, Tartu University Hospital, Tartu 50406, Estonia
18Institute of Clinical Medicine, University of Tartu, Tartu 50406, Estonia
19Department of Genomics and Clinical Genetics, Turku University Hospital, Turku 20500, Finland
20Department of Child Neurology, Turku University Hospital, Turku 20500, Finland
21Centre for Neurological Diseases, West-Tallinn Central Hospital, Tallinn 10617, Estonia
22Division of Genetic Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, 1011 Lausanne, Switzerland
23Division of Child and Adolescent Neuropsychiatry, University of Siena, Siena 53100, Italy
24Clinical Paediatrics, Department of Molecular Medicine and Development, University of Siena, Siena 53100, Italy
25IRCCS Stella Maris Foundation, Department of Developmental Neuroscience, Pisa 98125, Italy
26Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56122, Italy
27Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena 53100, Italy
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.4 MB)
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Language: English
Published: Oxford University Press, 2022
Publish Date: 2022-10-27


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.

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Series: Human molecular genetics
ISSN: 0964-6906
ISSN-E: 1460-2083
ISSN-L: 0964-6906
DOI: 10.1093/hmg/ddac167
Type of Publication: A1 Journal article – refereed
Field of Science: 1184 Genetics, developmental biology, physiology
Funding: K.Õ., T.R., K.M. and L.R. were supported by Estonian Research Council grant PRG471.
Copyright information: © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact