Case Report ARTICLE
RECURRENCE AND FAMILIAL INHERITANCE OF INTRONIC NIPBL PATHOGENIC VARIANT ASSOCIATED WITH MILD CDLS
- 1Laboratorio di Ricerche di Citogenetica Medica e Genetica Molecolare, Istituto Auxologico Italiano (IRCCS), Italy
- 2Azienda Ospedaliero Universitaria Ospedali Riuniti, Italy
- 3Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IRCCS), Italy
- 4U.O.C. Medical Genetics, Istituto Giannina Gaslini (IRCCS), Italy
Splicing mutations account for a notable fraction of NIPBL alterations underlying Cornelia de Lange syndrome but are likely underrepresented, due to overlooking of deep intronic variants by traditional and contemporary sequencing methods. We describe five subjects, belonging to three families, displaying a mild Cornelia de Lange syndrome phenotype who carry the NIPBL mutation c.5329-15A>G, affecting the IVS27 branch site, yet reported in a single case. By RNA analysis we evidenced two alternative transcripts: the exon 28 in frame skipped transcript, described in the published case and also an out-of-frame transcript retaining 14 nucleotides of IVS27 3’end. Even if both aberrant transcripts are at negligible levels, their presence justifies the CdLS phenotype shared by our patients consisting of borderline-mild cognitive impairment and slight but typical facial dysmorphisms. Transmission of the pathogenic variant from pauci symptomatic mother to her siblings emphasizes the need of molecular diagnosis also extended to deep intronic regions in patients with subtle but recognizable CdLS phenotype.
Keywords: Cornelia de Lange, Familial inheritance, recurrent variant, deep intronic variant, Mild phenotype
Received: 12 Sep 2018;
Accepted: 29 Oct 2018.
Edited by:Kette D. Valente, Universidade de São Paulo, Brazil
Reviewed by:Gemma L. Carvill, Northwestern University, United States
Anna L. Pinto, Department of Neurology, Boston Children's Hospital, United States
Felippe Borlot, University of Utah, United States
Copyright: © 2018 Masciadri, Ficcadenti, Milani, Cogliati, Divizia, Larizza and Russo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. Silvia Russo, Istituto Auxologico Italiano (IRCCS), Laboratorio di Ricerche di Citogenetica Medica e Genetica Molecolare, Milan, Lombardy, Italy, email@example.com