NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

Ina Schanze; Jens Bunt; Jonathan W.C. Lim; Denny Schanze; Ryan Dean; Marielle Alders; Patricia Blanchet; Tania Attié-Bitach; Siren Berland; Steven Boogert; Sangamitra Boppudi; Caitlin Bridges; Megan Cho; William Dobyns; Dian Donnai; Jessica Douglas; Dawn Earl; Timothy Edwards; Laurence Faivre; Brieana Fregeau; David Geneviève; Marion Gérard; Vincent Gatinois; Muriel Holder-Espinasse; Samuel Huth; Kosuke Izumi; Bronwyn Kerr; Elodie Lacaze; Phillis Lakeman; Sonal Mahida; Ghayda Mirzaa; Sian Morgan; Catherine Nowak; Hilde Peeters; Florence Petit; Daniela Pilz; Jacques Puechberty; Eyal Reinstein; Jean-Baptiste Rivière; Avni Santani; Anouck Schneider; Elliott Sherr; Constance Smith-Hicks; Ilse Wieland; Elaine Zackai; Xiaonan Zhao; Richard Gronostajski; Martin Zenker; Linda Richards

doi:10.1016/j.ajhg.2018.10.006

Article dans une revue

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 MCGM - 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 Montpellier]

18 Unité fonctionnelle de génétique clinique

19 Service de Génétique [CHU 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

Type de document :

Article dans une revue

Domaine :

Sciences du Vivant [q-bio] / Génétique / Génétique humaine

Liste complète des métadonnées

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 19 août 2020 - 11:17:50

NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

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