title: Broadening of cohesinopathies: exome sequencing identifies mutations in ANKRD11 in two patients with Cornelia de Lange-overlapping phenotype.
abstract: Cornelia de Lange syndrome (CdLS) and KBG syndrome are two distinct developmental pathologies sharing common features such as intellectual disability, psychomotor delay, and some craniofacial and limb abnormalities. Mutations in one of the five genes NIPBL, SMC1A, SMC3, HDAC8 or RAD21, were identified in at least 70% of the patients with CdLS. Consequently, additional causative genes, either unknown or responsible of partially merging entities, possibly account for the remaining 30% of the patients. In contrast, KBG has only been associated with mutations in ANKRD11. By exome sequencing we could identify heterozygous loss-of-function mutations in ANKRD11 in two patients with the clinical diagnosis of CdLS. Both patients show features reminiscent of CdLS such as characteristic facies as well as a small head circumference which is not described for KBG syndrome. Patient A, who carries the mutation in a mosaic state, is a 4-year-old girl with features reminiscent of CdLS. Patient B, a 15-year-old boy, shows a complex phenotype which resembled CdLS during infancy, but has developed to a more KBG overlapping phenotype during childhood. These findings point out the importance of screening ANKRD11 in young CdLS patients who were found to be negative for mutations in the five known CdLS genes.
authors: Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.|Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany.
authors: I
authors: I
authors: Parenti
authors: Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
authors: C
authors: C
authors: Gervasini
authors: Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany.
authors: J
authors: J
authors: Pozojevic
authors: Ambulantes Gesundheitszentrum der Charité Campus Virchow, Humangenetik, Universitätsmedizin Berlin, Berlin, Germany.
authors: L
authors: L
authors: Graul-Neumann
authors: Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
authors: J
authors: J
authors: Azzollini
authors: Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany.
authors: D
authors: D
authors: Braunholz
authors: Institut de Génétique et Développement de Rennes, Faculté de Médecine, UMR6290-CNRS, Rennes, France.
authors: E
authors: E
authors: Watrin
authors: Department of Cell Biology, Erasmus MC, Rotterdam, Netherlands.
authors: K S
authors: KS
authors: Wendt
authors: A.O. S.Gerardo, U.O.S. Genetica Clinica Pediatrica, Clinica Pediatrica Fondazione MBBM, Monza, Italy.
authors: A
authors: A
authors: Cereda
authors: Centre for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy.
authors: D
authors: D
authors: Cittaro
authors: Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany.
authors: G
authors: G
authors: Gillessen-Kaesbach
authors: Centre for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy.
authors: D
authors: D
authors: Lazarevic
authors: A.O. S.Gerardo, U.O.S. Genetica Clinica Pediatrica, Clinica Pediatrica Fondazione MBBM, Monza, Italy.
authors: M
authors: M
authors: Mariani
authors: Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy.
authors: S
authors: S
authors: Russo
authors: Department of Paediatrics and Adolescent Medicine, Division of Experimental Paediatric Endocrinology and Diabetes, University of Lübeck, Lübeck, Germany.
authors: R
authors: R
authors: Werner
authors: Ambulantes Gesundheitszentrum der Charité Campus Virchow, Humangenetik, Universitätsmedizin Berlin, Berlin, Germany.|Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors: P
authors: P
authors: Krawitz
authors: Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.|Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy.
authors: L
authors: L
authors: Larizza
authors: A.O. S.Gerardo, U.O.S. Genetica Clinica Pediatrica, Clinica Pediatrica Fondazione MBBM, Monza, Italy.
authors: A
authors: A
authors: Selicorni
authors: Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany.
authors: F J
authors: FJ
authors: Kaiser
mesh_terms: D000293:Adolescent; D002675:Child, Preschool; D003635:De Lange Syndrome / Q000175:diagnosis* / Q000235:genetics*; D059472:Exome; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: C492515:ANKRD11 protein, human; D012097:Repressor Proteins
keywords: ANKRD11; Cornelia de Lange syndrome; KBG syndrome; cohesin; mosaicism; whole exome sequencing