title: A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome.
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 a heterozygous NIPBL mutation identified by Sanger sequencing. The diagnosis was based on the following criteria: (i) intrauterine growth retardation and postnatal short stature, (ii) feeding difficulties and/or gastro-oesophageal reflux, (iii) microcephaly, (iv) intellectual disability, and (v) characteristic facial features. We identified 37 novel NIPBL mutations including 34 in leukocytes and 3 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 20 cases which do 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 counselling.
authors.affiliation: Département de Génétique, Université Paris Descartes-Sorbonne Paris Cité, INSERM UMR1163, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Nizon
authors.affiliation: Département de Génétique, Université Paris Descartes-Sorbonne Paris Cité, INSERM UMR1163, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Henry
authors.affiliation: Département de Génétique, Université Paris Descartes-Sorbonne Paris Cité, INSERM UMR1163, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Michot
authors.affiliation: Département de Génétique, CHU Robert Debré, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Baumann
authors.affiliation: Département de Génétique, CH René Dubos, Pontoise, France.
authors.forename: A
authors.initials: A
authors.lastname: Bazin
authors.affiliation: Département de Génétique, Université Paris Descartes-Sorbonne Paris Cité, INSERM UMR1163, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Bessières
authors.affiliation: Service de Génétique, CHRU Tours, Hôpital Bretonneau, Tours, France.
authors.forename: S
authors.initials: S
authors.lastname: Blesson
authors.affiliation: Service de Génétique Clinique, Hospices Civils de Lyon, Bron, France.
authors.forename: M-P
authors.initials: MP
authors.lastname: Cordier-Alex
authors.affiliation: Service de Génétique Médicale, CHU, Nantes, France.
authors.forename: A
authors.initials: A
authors.lastname: David
authors.affiliation: Service de Génétique, CHU Paris Seine-Saint-Denis, Hôpital Jean Verdier, Bondy, France.
authors.forename: A
authors.initials: A
authors.lastname: Delahaye-Duriez
authors.affiliation: Département de Génétique, CHU Robert Debré, Paris, France.
authors.forename: A-L
authors.initials: AL
authors.lastname: Delezoïde
authors.affiliation: Service de Génétique Clinique, CHRU de Lille, Hôpital Jeanne de Flandre, Lille, France.
authors.forename: A
authors.initials: A
authors.lastname: Dieux-Coeslier
authors.affiliation: Service de Génétique, CHU de Reims, Hôpital Maison Blanche, Reims, France.
authors.forename: M
authors.initials: M
authors.lastname: Doco-Fenzy
authors.affiliation: Centre de Génétique, CHU de Dijon, Dijon, France.
authors.forename: L
authors.initials: L
authors.lastname: Faivre
authors.affiliation: Département de Génétique, CHU, Rouen, France.
authors.forename: A
authors.initials: A
authors.lastname: Goldenberg
authors.affiliation: Service de Génétique Médicale, GH du Havre, Hôpital Jacques Monod, Le Havre, France.
authors.forename: V
authors.initials: V
authors.lastname: Layet
authors.affiliation: Service d'anatomie et cytologie pathologiques, Hôpital Pontchaillou, Université de Rennes 1, CHU, Rennes, France.
authors.forename: P
authors.initials: P
authors.lastname: Loget
authors.affiliation: Département de Génétique, Université Paris Descartes-Sorbonne Paris Cité, INSERM UMR1163, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Marlin
authors.affiliation: Département de Génétique, Université Paris Descartes-Sorbonne Paris Cité, INSERM UMR1163, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Martinovic
authors.affiliation: Service de Génétique Clinique, CHU Rennes, Hôpital Sud, Rennes, France.
authors.forename: S
authors.initials: S
authors.lastname: Odent
authors.affiliation: Service de Génétique Clinique, CHU Rennes, Hôpital Sud, Rennes, France.
authors.forename: L
authors.initials: L
authors.lastname: Pasquier
authors.affiliation: Service de Génétique Médicale, CHU Clémenceau, Caen, France.
authors.forename: G
authors.initials: G
authors.lastname: Plessis
authors.affiliation: Service de Génétique Clinique, CHU de Saint-Etienne, Hôpital Nord, Saint-Priest-en-Jarez, France.
authors.forename: F
authors.initials: F
authors.lastname: Prieur
authors.affiliation: Service de Génétique Clinique, Hospices Civils de Lyon, Bron, France.
authors.forename: A
authors.initials: A
authors.lastname: Putoux
authors.affiliation: Département de Génétique, Université Paris Descartes-Sorbonne Paris Cité, INSERM UMR1163, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Rio
authors.affiliation: Département de Pédiatrie, CHU Grenoble, Grenoble, France.
authors.forename: H
authors.initials: H
authors.lastname: Testard
authors.affiliation: Département de Génétique, Université Paris Descartes-Sorbonne Paris Cité, INSERM UMR1163, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: J-P
authors.initials: JP
authors.lastname: Bonnefont
authors.affiliation: Département de Génétique, Université Paris Descartes-Sorbonne Paris Cité, INSERM UMR1163, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D018797:Cell Cycle Proteins; D003635:De Lange Syndrome / Q000175:diagnosis / Q000235:genetics*; D005145:Face / Q000002:abnormalities*; D005146:Facial Asymmetry / Q000175:diagnosis / Q000235:genetics*; D019066:Facies; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D009061:Mouth Mucosa / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D018797:Cell Cycle Proteins; C487465:NIPBL protein, human; D011506:Proteins
keywords: Cornelia de Lange syndrome; NIPBL; buccal cells; somatic mosaicism