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A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome

Mathilde Nizon 1 Marcia Henry 1 Caroline Michot 1 Clarisse Baumann 2 Anne Bazin 3 Bettina Bessieres 1 Sophie Blesson 4 Marie-Pierre Cordier-Alex 5 Albert David 6 Andrée Delahaye-Duriez 7 Anne-Lise Delezoide 8 Anne Dieux-Coeslier 9 Martine Doco-Fenzy 10 Laurence Faivre 11 Alice Goldenberg 12 Valérie Layet 13 Philippe Loget 14 Sandrine Marlin 1 Jelena Martinovic 1 Sylvie Odent 15, 16 Laurent Pasquier 16 Ghislaine Plessis 17 Fabienne Prieur 18 Audrey Putoux 5 Marlène Rio 1 Hervé Testard 19 Jean-Paul Bonnefont 1 Valérie Cormier-Daire 1
Abstract : Cornelia de Lange syndrome is a multisystemic developmental disorder mainly related to de novo heterozygous NIPBL mutation. Recently, NIPBL somatic mosaicism has been highlighted through buccal cell DNA study in some patients with a negative molecular analysis on leukocyte DNA. Here, we present a series of 38 patients with a Cornelia de Lange syndrome related to an heterozygous NIPBL mutation identified by Sanger sequencing. The diagnosis was based on the following criteria: 1) intrauterine growth retardation and postnatal short stature, 2) feeding difficulties and/or gastro-oesophageal reflux, 3) microcephaly, 4) intellectual disability and 5) characteristic facial features. We identified 37 novel NIPBL mutations including 34 in leukocytes and three in buccal cells only. All mutations shown to have arisen de novo when parent blood samples were available. The present series confirms the difficulty in predicting the phenotype according to the NIPBL mutation. Until now, somatic mosaicism has been observed for twenty cases which does not seem to be consistently associated with a milder phenotype. Besides, several reports support a postzygotic event for those cases. Considering these elements, we recommend a first-line buccal cell DNA analysis in order to improve gene testing sensitivity in Cornelia de Lange syndrome and genetic counseling
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Mathilde Nizon, Marcia Henry, Caroline Michot, Clarisse Baumann, Anne Bazin, et al.. A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome. Clinical Genetics, Wiley, 2016, 89 (5), pp.584-589. ⟨10.1111/cge.12720⟩. ⟨hal-01255844⟩

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