TY - JOUR
T1 - NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly
AU - Schanze, Ina
AU - Bunt, Jens
AU - Lim, Jonathan W.C.
AU - Schanze, Denny
AU - Dean, Ryan J.
AU - Alders, Marielle
AU - Blanchet, Patricia
AU - Attié-Bitach, Tania
AU - Berland, Siren
AU - Boogert, Steven
AU - Boppudi, Sangamitra
AU - Bridges, Caitlin J.
AU - Cho, Megan T.
AU - Dobyns, William B.
AU - Donnai, Dian
AU - Douglas, Jessica
AU - Earl, Dawn L.
AU - Edwards, Timothy J.
AU - Faivre, Laurence
AU - Fregeau, Brieana
AU - Genevieve, David
AU - Gérard, Marion
AU - Gatinois, Vincent
AU - Holder-Espinasse, Muriel
AU - Huth, Samuel F.
AU - Izumi, Kosuke
AU - Kerr, Bronwyn
AU - Lacaze, Elodie
AU - Lakeman, Phillis
AU - Mahida, Sonal
AU - Mirzaa, Ghayda M.
AU - Morgan, Sian M.
AU - Nowak, Catherine
AU - Peeters, Hilde
AU - Petit, Florence
AU - Pilz, Daniela T.
AU - Puechberty, Jacques
AU - Reinstein, Eyal
AU - Rivière, Jean Baptiste
AU - Santani, Avni B.
AU - Schneider, Anouck
AU - Sherr, Elliott H.
AU - Smith-Hicks, Constance
AU - Wieland, Ilse
AU - Zackai, Elaine
AU - Zhao, Xiaonan
AU - Gronostajski, Richard M.
AU - Zenker, Martin
AU - Richards, Linda J.
N1 - Funding Information:
This work was supported by grants from the National Health and Medical Research Council Australia ( GNT1100443 to L.J.R.), the French Ministry of Health (PHRC national 2008/2008-A00515-50 ), Regional Council of Burgundy/Dijon University hospital ( PARI 2012 ), The Genesis Foundation for Children , the US National Institutes of Health under NINDS grants ( 1R01NS092772 and 234567890 to W.B.D.; 1R01NS058721 to W.B.D. and E.H.S.; and K08NS092898 to G.M.M.), and Jordan’s Guardian Angels (G.M.M.). J.W.C.L. was supported by an International Postgraduate Research Scholarship and UQ Centennial Scholarship . R.M.G. was supported by NYSTEM grants ( C026714 , C026429 , and C030133 ). R.J.D. was supported by Brain Injured Children’s Aftercare Recovery Endeavours (BICARE) Fellowship. L.J.R. was supported by an NHMRC Principal Research Fellowship ( GNT1005751 ). M.Z. was supported by a grant from the German Ministry of Education and Research (BMBF) ( GeNeRARe 01GM1519A ). We acknowledge the Linkage Infrastructure, Equipment and Facilities (LIEF) grant ( LE100100074 ) awarded to the Queensland Brain Institute for the Slide Scanner and the facilities of the National Imaging Facility (NIF) at the Centre for Advanced Imaging, University of Queensland, used in the animal experiments. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding sources.
Funding Information:
This work was supported by grants from the National Health and Medical Research Council Australia (GNT1100443 to L.J.R.), the French Ministry of Health (PHRC national 2008/2008-A00515-50), Regional Council of Burgundy/Dijon University hospital (PARI 2012), The Genesis Foundation for Children, the US National Institutes of Health under NINDS grants (1R01NS092772 and 234567890 to W.B.D.; 1R01NS058721 to W.B.D. and E.H.S.; and K08NS092898 to G.M.M.), and Jordan's Guardian Angels (G.M.M.). J.W.C.L. was supported by an International Postgraduate Research Scholarship and UQ Centennial Scholarship. R.M.G. was supported by NYSTEM grants (C026714, C026429, and C030133). R.J.D. was supported by Brain Injured Children's Aftercare Recovery Endeavours (BICARE) Fellowship. L.J.R. was supported by an NHMRC Principal Research Fellowship (GNT1005751). M.Z. was supported by a grant from the German Ministry of Education and Research (BMBF) (GeNeRARe 01GM1519A). We acknowledge the Linkage Infrastructure, Equipment and Facilities (LIEF) grant (LE100100074) awarded to the Queensland Brain Institute for the Slide Scanner and the facilities of the National Imaging Facility (NIF) at the Centre for Advanced Imaging, University of Queensland, used in the animal experiments. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding sources.
Publisher Copyright:
© 2018 American Society of Human Genetics
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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.
AB - 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.
KW - NFIB
KW - agenesis of the corpus callosum
KW - chromosome 9p22.3
KW - chromosome 9p23
KW - developmental delay
KW - haploinsufficiency
KW - intellectual disability
KW - macrocephaly
KW - megalencephaly
KW - nuclear factor I
UR - http://www.scopus.com/inward/record.url?scp=85055481130&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2018.10.006
DO - 10.1016/j.ajhg.2018.10.006
M3 - Article
C2 - 30388402
AN - SCOPUS:85055481130
VL - 103
SP - 752
EP - 768
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 5
ER -