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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, 10 Dian Donnai 11 Jessica Douglas 12 Dawn Earl 10 Timothy Edwards 2 Laurence Faivre 13, 14, 15 Brieana Fregeau 16 David Geneviève 5, 4 Marion Gérard 17, 18 Vincent Gatinois 4, 5 Muriel Holder-Espinasse 19 Samuel Huth 2 Kosuke Izumi 20 Bronwyn Kerr 11 Elodie Lacaze 21 Phillis Lakeman 3 Sonal Mahida 22 Ghayda Mirzaa 10 Sian Morgan 23 Catherine Nowak 24 Hilde Peeters 25 Florence Petit 19 Daniela Pilz 26 Jacques Puechberty 4, 5 Eyal Reinstein 27 Jean-Baptiste Rivière 14, 13, 15 Avni Santani 20 Anouck Schneider 4, 5 Elliott Sherr 16 Constance Smith-Hicks 22 Ilse Wieland 1 Elaine Zackai 20, 28 Xiaonan Zhao 20 Richard Gronostajski Martin Zenker 1, * Linda Richards 29
* Auteur correspondant
1 OVGU - Otto-von-Guericke University [Magdeburg]
2 Queensland Brain Institute
3 UvA - University of Amsterdam [Amsterdam]
4 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
5 Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier]
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 University of Washington [Seattle]
10 Seattle Children’s Hospital
11 University of Manchester [Manchester]
12 Boston Children's Hospital
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 UCSF - University of California [San Francisco]
17 Unité fonctionnelle de génétique clinique
18 Service de Génétique [CHU Caen]
19 CHU Lille
20 CHOP - Children’s Hospital of Philadelphia
21 Département de génétique (groupe hospitalier le Havre)
22 Kennedy Krieger Institute [Baltimore]
23 University Hospital of Wales [Cardiff, UK]
24 Boston Children's Hospital
25 University Hospitals Leuven [Leuven]
26 University of Glasgow
27 Sackler Faculty of Medicine
28 Perelman School of Medicine
29 University of Queensland [Brisbane]
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
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Soumis le : mercredi 30 janvier 2019 - 09:52:41
Dernière modification le : lundi 3 janvier 2022 - 11:40:39

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UNIV-BOURGOGNE | USPC | LNC-UMR866 | LNC-GAD | BS | UNIV-MONTPELLIER | UNIV-PARIS5 | UNIV-PARIS7 | COMUE-NORMANDIE | UNICAEN | INSERM | UNIV-PARIS | UP-SANTE

Citation

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. ⟨10.1016/j.ajhg.2018.10.006⟩. ⟨hal-01999378⟩

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