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Clin Genet. 2016 Jan;89(1):74-81. doi: 10.1111/cge.12564. Epub 2015 Feb 25.

Broadening of cohesinopathies: exome sequencing identifies mutations in ANKRD11 in two patients with Cornelia de Lange-overlapping phenotype.

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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.
Ambulantes Gesundheitszentrum der Charité Campus Virchow, Humangenetik, Universitätsmedizin Berlin, Berlin, Germany.
Institut de Génétique et Développement de Rennes, Faculté de Médecine, UMR6290-CNRS, Rennes, France.
Department of Cell Biology, Erasmus MC, Rotterdam, Netherlands.
A.O. S.Gerardo, U.O.S. Genetica Clinica Pediatrica, Clinica Pediatrica Fondazione MBBM, Monza, Italy.
Centre for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy.
Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany.
Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy.
Department of Paediatrics and Adolescent Medicine, Division of Experimental Paediatric Endocrinology and Diabetes, University of Lübeck, Lübeck, Germany.
Max Planck Institute for Molecular Genetics, Berlin, Germany.


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.


ANKRD11; Cornelia de Lange syndrome; KBG syndrome; cohesin; mosaicism; whole exome sequencing

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