Duplications of the critical Rubinstein-Taybi deletion region on chromosome 16p13.3 cause a novel recognizable syndrome

Bernard Thienpont¹, Frédérique Béna², Jeroen Breckpot¹, Nicole Philip³, Björn Menten⁴, Hilde Van Esch¹, Emmanuel Scalais⁵, Jessica Salamone⁶, Chin-To Fong⁶, Jennifer L Kussmann⁷, Dorothy K Grange⁸, Jerome Gorski⁷, Farah Zahir⁹, Siu Li Yong¹⁰, Michael M Morris², Stefania Gimelli², Jean-Pierre Fryns¹, Geert Mortier⁴, Jan M Friedman⁹, Laurent Villard¹¹, Armand Bottani², Joris R Vermeesch¹, Sau Wai Cheung¹², Koen Devriendt^1,*

¹ Center for Human Genetics, K.U.Leuven, Leuven, Belgium;
² Service of Genetic Medicine, Geneva University Hospitals, Geneva, Switzerland;
³ CRADSM PACA, Département de génétique médicale, Hôpital d'Enfants de la Timone, Marseille, Belgium;
⁴ Center for Medical Genetics, Ghent University Hospital, Ghent, France;
⁵ Paediatric Neurology, Department of Paediatrics, Centre Hospitalier de Luxembourg, Belgium;
⁶ Departments of Pediatrics and of Medicine, University of Rochester, Rochester, New York, Belgium;
⁷ Department of Child Health, University of Missouri School of Medicine, Columbia, Missouri, Luxembourg;
⁸ Div Genetics & Genomic Medicine, Dept of Pediatrics, Washington Univ School of Medicine, St Louis, United States;
⁹ Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, United States;
¹⁰ Medical Genetics, Child and Family Research Institute, Children's and Women's Hospital, Vancouver, United States;
¹¹ Faculté de Médecine de La Timone, Inserm Unité 910, Université de la Méditerranée, Marseille, United States;
¹² Cytogenetic and Microarray Laboratories, Dept Molecular and Human Genetics, Baylor College, Houston, United States

Correspondence to: Koen HMT Devriendt, KU Leuven, Herestraat 49, Leuven, B-3000, Belgium; koen.devriendt{at}med.kuleuven.be

Accepted 19 July 2009

The introduction of molecular karyotyping technologies facilitated the identification of specific genetic disorders associated with imbalances of certain genomic regions. A detailed phenotypic delineation of interstitial 16p13.3 duplications is hampered by the scarcity of such patients. The present report describes the genotypic and phenotypic delineation of nine submicroscopic interstitial 16p13.3 duplications. Such duplications have a recognizable phenotype, characterized by normal to moderately retarded mental development, normal growth, mild arthrogryposis, frequently small and proximally implanted thumbs and characteristic facial features. Occasionally, developmental defects of the heart, genitalia, palate or the eyes are observed. The critically duplicated region encompasses a single gene, CREBBP, which is mutated or deleted in Rubinstein-Taybi syndrome. In 10 out of the 12 hitherto described probands, the duplication arose de novo, demonstrating the reduced reproductive fitness associated with this genotype. Inheritance of the duplication from a clinically normal parent in two cases indicates that the associated phenotype is incompletely penetrant.

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