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Am J Hum Genet. 2018 Nov 1;103(5):752-768. doi: 10.1016/j.ajhg.2018.10.006.

NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly.

Author information

1
Institute of Human Genetics, University Hospital Magdeburg, Otto-von-Guericke University, Magdeburg 39120, Germany.
2
Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: j.bunt@uq.edu.au.
3
Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
4
Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
5
INSERM U1183, Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Génétique clinique, CHU Montpellier, Université Montpellier, Centre de référence anomalies du développement SORO, Montpellier 34295, France.
6
INSERM U1163, Laboratory of Embryology and Genetics of Congenital Malformations, Paris Descartes University, Sorbonne Paris Cité and Imagine Institute, Paris 75015, France.
7
Department of Medical Genetics, Haukeland University Hospital, Bergen 5021, Norway.
8
GeneDx, Gaithersburg, MD 20877, USA.
9
Department of Pediatrics (Genetics), University of Washington and Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
10
Manchester Centre for Genomic Medicine, Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust; Division of Evolution and Genomic Sciences School of Biological Sciences, and University of Manchester, Manchester M13 9WL, UK.
11
Boston Children's Hospital - The Feingold Center, Waltham, MA 02115, USA.
12
Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.
13
Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia; The Faculty of Medicine Brisbane, The University of Queensland, Brisbane, QLD 4072, Australia.
14
UMR1231, Génétique des Anomalies du Développement, Université de Bourgogne, Dijon 21079, France; Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est et FHU TRANSLAD, Centre Hospitalier Universitaire Dijon, Dijon 21079, France.
15
Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
16
Service de Génétique, CHU de Caen - Hôpital Clémenceau, Caen Cedex 14000, France.
17
Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHU Lille, Lille 59000, France; Department of Clinical Genetics, Guy's Hospital, London SE1 9RT, UK.
18
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
19
Department of genetics, Le Havre Hospital, 76600 Le Havre, France.
20
Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
21
All Wales Genetics Laboratory, Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK.
22
Center for Human Genetics, University Hospital Leuven, KU Leuven, Leuven 3000, Belgium.
23
Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHU Lille, Lille 59000, France.
24
West of Scotland Genetics Service, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.
25
Medical Genetics Institute, Meir Medical Center, Kfar-Saba 4428164, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
26
UMR1231, Génétique des Anomalies du Développement, Université de Bourgogne, Dijon 21079, France; Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est et FHU TRANSLAD, Centre Hospitalier Universitaire Dijon, Dijon 21079, France; Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
27
Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
28
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
29
Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
30
Department of Biochemistry, Program in Genetics, Genomics and Bioinformatics, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA.
31
Institute of Human Genetics, University Hospital Magdeburg, Otto-von-Guericke University, Magdeburg 39120, Germany. Electronic address: martin.zenker@med.ovgu.de.
32
Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia; School of Biomedical Sciences, The Faculty of Medicine Brisbane, The University of Queensland, Brisbane, QLD 4072, Australia.

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; agenesis of the corpus callosum; chromosome 9p22.3; chromosome 9p23; developmental delay; haploinsufficiency; intellectual disability; macrocephaly; megalencephaly; nuclear factor I

PMID:
30388402
PMCID:
PMC6218805
[Available on 2019-05-01]
DOI:
10.1016/j.ajhg.2018.10.006

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