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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 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
6 Equipe Inserm U1163 - Embryology and genetics of human malformation
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
14 Equipe GAD (LNC - U1231)
LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
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.
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Contributeur : Lnc - Université de Bourgogne <>
Soumis le : mercredi 30 janvier 2019 - 09:52:41
Dernière modification le : mardi 29 juin 2021 - 03:23:51

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



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