Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/101881
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Type: Journal article
Title: Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism
Author: Ansari, M.
Poke, G.
Ferry, Q.
Williamson, K.
Aldridge, R.
Meynert, A.
Bengani, H.
Chan, C.
Kayserili, H.
Avci, Ş.
Hennekam, R.
Lampe, A.
Redeker, E.
Homfray, T.
Ross, A.
Smeland, M.
Mansour, S.
Parker, M.
Cook, J.
Splitt, M.
et al.
Citation: Journal of Medical Genetics, 2014; 51(10):659-668
Publisher: BMJ Publishing Group
Issue Date: 2014
ISSN: 0022-2593
1468-6244
Statement of
Responsibility: 
Morad Ansari ... Elizabeth M Thompson ... et al
Abstract: Background: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS. Methods: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing. Results: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as ‘NIPBL-like’. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutationnegative group supporting the existence of undetected mosaic cases. Conclusions: Future diagnostic testing in ‘mutationnegative’ CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.
Keywords: De Lange Syndrome
Rights: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/
RMID: 0030014962
DOI: 10.1136/jmedgenet-2014-102573
Appears in Collections:Medicine publications

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