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Genomic imbalances in patients with a clinical presentation in the spectrum of Cornelia de Lange syndrome

Cristina Gervasini1, Chiara Picinelli2, Jacopo Azzollini1, Daniela Rusconi26, Maura Masciadri2, Anna Cereda3, Cinzia Marzocchi4, Giuseppe Zampino5, Angelo Selicorni3, Romano Tenconi4, Silvia Russo2, Lidia Larizza12 and Palma Finelli267*

Author Affiliations

1 Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy

2 Laboratory of Medical Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano, Milan, Italy

3 Pediatric Department, Università Milano Bicocca, Fondazione MBBM, S. Gerardo Hospital, Monza, Italy

4 Genetica Clinica Epidemiologica, Dipartimento Pediatria, Padua, Italy

5 Department of Pediatrics, Catholic University, Rome, Italy

6 Deptartment of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy

7 Department of Medical Biotechnology and Translational Medicine, C/O Laboratory of Medical Cytogenetics and Molecular Genetics, Centro d Ricerche e Tecnologie Biomediche, IRCCS-Istituto Auxologico Italiano, via Zucchi 18, Cusano Milanino, MI 20095, Italy

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BMC Medical Genetics 2013, 14:41  doi:10.1186/1471-2350-14-41

Published: 3 April 2013



Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant disorder characterised by facial dysmorphism, growth and psychomotor developmental delay and skeletal defects. To date, causative mutations in the NIPBL (cohesin regulator) and SMC1A (cohesin structural subunit) genes account for > 50% and 6% of cases, respectively.


We recruited 50 patients with a CdLS clinical diagnosis or with features that overlap with CdLS, who were negative for mutations at NIPBL and SMC1A at molecular screening. Chromosomal rearrangements accounting for the clinical diagnosis were screened for using array Comparative Genomic Hybridisation (aCGH).


Four patients were shown to carry imbalances considered to be candidates for having pathogenic roles in their clinical phenotypes: patient 1 had a 4.2 Mb de novo deletion at chromosome 20q11.2-q12; patient 2 had a 4.8 Mb deletion at chromosome 1p36.23-36.22; patient 3 carried an unbalanced translocation, t(7;17), with a 14 Mb duplication of chromosome 17q24.2-25.3 and a 769 Kb deletion at chromosome 7p22.3; patient 4 had an 880 Kb duplication of chromosome 19p13.3, for which his mother, who had a mild phenotype, was also shown to be a mosaic.


Notwithstanding the variability in size and gene content of the rearrangements comprising the four different imbalances, they all map to regions containing genes encoding factors involved in cell cycle progression or genome stability. These functional similarities, also exhibited by the known CdLS genes, may explain the phenotypic overlap between the patients included in this study and CdLS. Our findings point to the complexity of the clinical diagnosis of CdLS and confirm the existence of phenocopies, caused by imbalances affecting multiple genomic regions, comprising 8% of patients included in this study, who did not have mutations at NIPBL and SMC1A. Our results suggests that analysis by aCGH should be recommended for CdLS spectrum cases with an unexplained clinical phenotype and included in the flow chart for diagnosis of cases with a clinical evaluation in the CdLS spectrum.