NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

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

doi:10.1016/j.ajhg.2018.10.006

NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

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

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

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.

Original language	English (US)
Pages (from-to)	752-768
Number of pages	17
Journal	American Journal of Human Genetics
Volume	103
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2018.10.006
State	Published - Nov 1 2018
Externally published	Yes

Bibliographical note

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

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ajhg.2018.10.006

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Schanze, I., Bunt, J., Lim, J. W. C., Schanze, D., Dean, R. J., Alders, M., Blanchet, P., Attié-Bitach, T., Berland, S., Boogert, S., Boppudi, S., Bridges, C. J., Cho, M. T., Dobyns, W. B., Donnai, D., Douglas, J., Earl, D. L., Edwards, T. J., Faivre, L., ... Richards, L. J. (2018). NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly. American Journal of Human Genetics, 103(5), 752-768. https://doi.org/10.1016/j.ajhg.2018.10.006

Schanze, I, Bunt, J, Lim, JWC, Schanze, D, Dean, RJ, Alders, M, Blanchet, P, Attié-Bitach, T, Berland, S, Boogert, S, Boppudi, S, Bridges, CJ, Cho, MT, Dobyns, WB, Donnai, D, Douglas, J, Earl, DL, Edwards, TJ, Faivre, L, Fregeau, B, Genevieve, D, Gérard, M, Gatinois, V, Holder-Espinasse, M, Huth, SF, Izumi, K, Kerr, B, Lacaze, E, Lakeman, P, Mahida, S, Mirzaa, GM, Morgan, SM, Nowak, C, Peeters, H, Petit, F, Pilz, DT, Puechberty, J, Reinstein, E, Rivière, JB, Santani, AB, Schneider, A, Sherr, EH, Smith-Hicks, C, Wieland, I, Zackai, E, Zhao, X, Gronostajski, RM, Zenker, M & Richards, LJ 2018, 'NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly', American Journal of Human Genetics, vol. 103, no. 5, pp. 752-768. https://doi.org/10.1016/j.ajhg.2018.10.006

@article{234314e1ae1e4fb392064e38c9d46474,

title = "NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly",

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",

author = "Ina Schanze and Jens Bunt and Lim, {Jonathan W.C.} and Denny Schanze and Dean, {Ryan J.} and Marielle Alders and Patricia Blanchet and Tania Atti{\'e}-Bitach and Siren Berland and Steven Boogert and Sangamitra Boppudi and Bridges, {Caitlin J.} and Cho, {Megan T.} and Dobyns, {William B.} and Dian Donnai and Jessica Douglas and Earl, {Dawn L.} and Edwards, {Timothy J.} and Laurence Faivre and Brieana Fregeau and David Genevieve and Marion G{\'e}rard and Vincent Gatinois and Muriel Holder-Espinasse and Huth, {Samuel F.} and Kosuke Izumi and Bronwyn Kerr and Elodie Lacaze and Phillis Lakeman and Sonal Mahida and Mirzaa, {Ghayda M.} and Morgan, {Sian M.} and Catherine Nowak and Hilde Peeters and Florence Petit and Pilz, {Daniela T.} and Jacques Puechberty and Eyal Reinstein and Rivi{\`e}re, {Jean Baptiste} and Santani, {Avni B.} and Anouck Schneider and Sherr, {Elliott H.} and Constance Smith-Hicks and Ilse Wieland and Elaine Zackai and Xiaonan Zhao and Gronostajski, {Richard M.} and Martin Zenker and Richards, {Linda J.}",

note = "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{\textquoteright}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{\textquoteright}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: {\textcopyright} 2018 American Society of Human Genetics",

year = "2018",

month = nov,

day = "1",

doi = "10.1016/j.ajhg.2018.10.006",

language = "English (US)",

volume = "103",

pages = "752--768",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "5",

}

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

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UR - http://www.scopus.com/inward/citedby.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

SN - 0002-9297

VL - 103

SP - 752

EP - 768

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 5

ER -

NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

Abstract

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Keywords

UN SDGs

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