NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

Ina Schanze 1 Jens Bunt 2, * Jonathan W.C. Lim 2 Denny Schanze 1 Ryan Dean 2 Marielle Alders 3 Patricia Blanchet 4, 5 Tania Attié-Bitach 6 Siren Berland 7 Steven Boogert 1 Sangamitra Boppudi 1 Caitlin Bridges 1 Megan Cho 8 William Dobyns 9 Dian Donnai 10 Jessica Douglas 11 Dawn Earl 12 Timothy Edwards 2 Laurence Faivre 13, 14, 15 Brieana Fregeau 16 David Geneviève 17, 5 Marion Gérard 18, 19 Vincent Gatinois 5, 17 Muriel Holder-Espinasse 20 Samuel Huth 2 Kosuke Izumi 21 Bronwyn Kerr 10 Elodie Lacaze 22 Phillis Lakeman 23 Sonal Mahida 24 Ghayda Mirzaa 25 Sian Morgan 26 Catherine Nowak 27 Hilde Peeters 28 Florence Petit 20 Daniela Pilz 29 Jacques Puechberty 5, 4 Eyal Reinstein 30 Jean-Baptiste Rivière 14, 13, 15 Avni Santani 31 Anouck Schneider 5 Elliott Sherr Constance Smith-Hicks Ilse Wieland Elaine Zackai 32 Xiaonan Zhao 33 Richard Gronostajski 34 Martin Zenker 35, * Linda Richards 36
* Auteur correspondant
1 Institute of Human Genetics (University Hospital Magdeburg)
2 Queensland Brain Institute
3 Department of Clinical Genetics, Academic Medical Centre, Amsterdam
4 Centre de Référence Anomalies du Développement et Syndromes Malformatifs (CHU de Montpellier)
5 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
6 Equipe Inserm U1163 - Embryology and genetics of human malformation
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
7 Haukeland University Hospital
8 GeneDx [Gaithersburg, MD, USA]
9 Seattle Children's Research Institute
10 Manchester Centre for Genomic Medicine
11 The Feingold Center for children (Boston Children’s Hospital)
12 Seattle Children’s Hospital [Seattle, WA, USA]
13 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
14 Equipe GAD (LNC - U1231)
LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
15 FHU TRANSLAD (CHU de Dijon)
16 Department of Neurology (University of California : San Francisco)
17 Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier]
18 Unité fonctionnelle de génétique clinique
19 Service de Génétique (CHU de Caen)
20 Service de génétique clinique (CHU Lille)
21 Department of Pediatrics (Perelman School of Medicine)
22 Département de génétique (groupe hospitalier le Havre)
23 Department of Clinical Genetics (Academic Medical Center, University of Amsterdam)
24 Kennedy Krieger Institute [Baltimore]
25 Division of Genetic Medicine - Department of Pediatrics [Seattle, WA, USA]
26 Institute of Medical Genetics (University Hospital of Wales)
27 Boston Children's Hospital
28 Center for Human Genetics, University Hospitals Leuven
29 West of Scotland Genetics Service (Queen Elizabeth University Hospital)
30 Sackler Faculty of Medicine
31 Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA]
32 Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia
33 CHOP - Children’s Hospital of Philadelphia
34 Department of Biochemistry and Developmental Genomics Group
35 Institute of Human Genetics
36 Queensland Brain Institute and School of Biomedical Sciences
Abstract : The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.
Keywords : NFIB intellectual disability nuclear factor I megalencephaly macrocephaly chromosome 9p22.3 agenesis of the corpus callosum chromosome 9p23 developmental delay haploinsufficiency
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01999378
Contributeur : Lnc - Université de Bourgogne <>
Soumis le : mercredi 30 janvier 2019 - 09:52:41
Dernière modification le : mercredi 26 juin 2019 - 19:24:02

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UNIV-BOURGOGNE | USPC | LNC-UMR866 | LNC-GAD | BS | UNIV-MONTPELLIER | UNIV-PARIS5 | UNIV-PARIS7

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Ina Schanze, Jens Bunt, Jonathan W.C. Lim, Denny Schanze, Ryan Dean, et al.. NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly. American Journal of Human Genetics, Elsevier (Cell Press), 2018, 103 (5), pp.752-768. ⟨https://www.sciencedirect.com/science/article/pii/S0002929718303586?via%3Dihub⟩. ⟨10.1016/j.ajhg.2018.10.006⟩. ⟨hal-01999378⟩

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