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BioMed Research International
Volume 2016, Article ID 8742939, 8 pages
Research Article

Identification and Functional Characterization of Two Intronic NIPBL Mutations in Two Patients with Cornelia de Lange Syndrome

1Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, School of Medicine, University of Zaragoza, CIBERER-GCV and ISS-Aragon, 50009 Zaragoza, Spain
2Section of Functional Genetics, Institute of Human Genetics, University of Lübeck, 23538 Lübeck, Germany
3Department of Health Sciences, Medical Genetics, University of Milan, 20122 Milan, Italy
4Department of Pediatrics, Pablo Tobon Uribe Hospital, 05001000 Medellín, Colombia
5Institute of Human Genetics, University of Lübeck, 23538 Lübeck, Germany
6Institute of Human Genetics, University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany

Received 3 October 2015; Accepted 16 November 2015

Academic Editor: Claude Prigent

Copyright © 2016 María E. Teresa-Rodrigo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Cornelia de Lange syndrome (CdLS) is a rare genetically heterogeneous disorder with a high phenotypic variability including mental retardation, developmental delay, and limb malformations. The genetic causes in about 30% of patients with CdLS are still unknown. We report on the functional characterization of two intronic NIPBL mutations in two patients with CdLS that do not affect a conserved splice-donor or acceptor site. Interestingly, mRNA analyses showed aberrantly spliced transcripts missing exon 28 or 37, suggesting the loss of the branch site by the c.5329-15A>G transition and a disruption of the polypyrimidine by the c.6344del(-13)_(-8) deletion. While the loss of exon 28 retains the reading frame of the NIBPL transcript resulting in a shortened protein, the loss of exon 37 shifts the reading frame with the consequence of a premature stop of translation. Subsequent quantitative PCR analysis demonstrated a 30% decrease of the total NIPBL mRNA levels associated with the frameshift transcript. Consistent with our results, this patient shows a more severe phenotype compared to the patient with the aberrant transcript that retains its reading frame. Thus, intronic variants identified by sequencing analysis in CdLS diagnostics should carefully be examined before excluding them as nonrelevant to disease.