CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

DDD Study

doi:10.1038/s41436-019-0585-z

CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

DDD Study

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45 Scopus citations

Abstract

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individualswith a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39subjects with variants in CTCF. We performedtranscriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impactof Ctcf dosage alteration on nervous systemdevelopment and function. Results: The individuals in our cohort carried 2 deletions, 8 likelygene-disruptive, 2 splice-site, and 20 different missense variants, most of themde novo. Two cases were familial. The associated phenotype was of variableseverity extending from mild developmental delay or normal IQ to severeintellectual disability. Feeding difficulties and behavioral abnormalities werecommon, and variable other findings including growth restriction and cardiacdefects were observed. RNA-sequencing in five individuals identified 3828deregulated genes enriched for known NDD genes and biological processes such astranscriptional regulation. Ctcf dosagealteration in Drosophila resulted in impairedgross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed lightonto the functional role of CTCF by identifying deregulated genes and show thatCtcf alterations result in nervous system defects in Drosophila.

Original language	English (US)
Pages (from-to)	2723-2733
Number of pages	11
Journal	Genetics in Medicine
Volume	21
Issue number	12
DOIs	https://doi.org/10.1038/s41436-019-0585-z
State	Published - Dec 1 2019

Bibliographical note

Funding Information:
We thank all individuals and families for participating in this study. We especially thank Laila Distel and Christine Suchy for excellent technical assistance; André Reis, Arif Ekici, and Fulvia Ferrazzi at the next-generation sequencing core facility at the Institute of Human Genetics in Erlangen; and Felix Engel for help with the confocal microscope, which was supported by the German Research Foundation (INST 410/91-1 FUGG). C.Z. is supported by grants from the German Research Foundation (ZW184/1-2, ZW184/3-1, and 270949263/GRK2162) and by the Interdisciplinary Center for Clinical Research in Erlangen (E26 and ELAN-Fonds). H.V.E. is a clinical investigator of FWO Vlaanderen. K.Õ. and S.P. received support from Estonian Research Council grants PUT355, PRG471, and PUTJD827. M.H.W. is supported by T32GM007748. This study makes use of data generated by the DECIPHER community. Funding for the project was provided by the Wellcome Trust. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. The Broad Center for Mendelian Genomics (UM1 HG008900) is funded by the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute. Please also see Supplementary Acknowledgements.

Publisher Copyright:
© 2019, The Author(s).

Keywords

CTCF
Drosophila melanogaster
chromatin organization
intellectual disability
neurodevelopmental disorders

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@article{841da7bd521140a2b6f0c0c2d8bfa541,

title = "CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum",

abstract = "Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individualswith a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39subjects with variants in CTCF. We performedtranscriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impactof Ctcf dosage alteration on nervous systemdevelopment and function. Results: The individuals in our cohort carried 2 deletions, 8 likelygene-disruptive, 2 splice-site, and 20 different missense variants, most of themde novo. Two cases were familial. The associated phenotype was of variableseverity extending from mild developmental delay or normal IQ to severeintellectual disability. Feeding difficulties and behavioral abnormalities werecommon, and variable other findings including growth restriction and cardiacdefects were observed. RNA-sequencing in five individuals identified 3828deregulated genes enriched for known NDD genes and biological processes such astranscriptional regulation. Ctcf dosagealteration in Drosophila resulted in impairedgross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed lightonto the functional role of CTCF by identifying deregulated genes and show thatCtcf alterations result in nervous system defects in Drosophila.",

keywords = "CTCF, Drosophila melanogaster, chromatin organization, intellectual disability, neurodevelopmental disorders",

author = "{DDD Study} and Konrad, {Enrico D.H.} and Niels Nardini and Almuth Caliebe and Inga Nagel and Dana Young and Gabriella Horvath and Santoro, {Stephanie L.} and Christine Shuss and Alban Ziegler and Dominique Bonneau and Marlies Kempers and Rolph Pfundt and Eric Legius and Arjan Bouman and Stuurman, {Kyra E.} and Katrin {\~O}unap and Sander Pajusalu and Wojcik, {Monica H.} and Georgia Vasileiou and {Le Guyader}, Gwena{\"e}l and Schnelle, {Hege M.} and Siren Berland and Evelien Zonneveld-Huijssoon and Simone Kersten and Aditi Gupta and Blackburn, {Patrick R.} and Ellingson, {Marissa S.} and Ferber, {Matthew J.} and Radhika Dhamija and Klee, {Eric W.} and Meriel McEntagart and Lichtenbelt, {Klaske D.} and Amy Kenney and Vergano, {Samantha A.} and {Abou Jamra}, Rami and Konrad Platzer and {Ella Pierpont}, Mary and Divya Khattar and Hopkin, {Robert J.} and Martin, {Richard J.} and Jongmans, {Marjolijn C.J.} and Chang, {Vivian Y.} and Martinez-Agosto, {Julian A.} and Outi Kuismin and Kurki, {Mitja I.} and Olli Pietil{\"a}inen and Aarno Palotie and Maarup, {Timothy J.} and Johnson, {Diana S.} and {Venborg Pedersen}, Katja",

note = "Funding Information: We thank all individuals and families for participating in this study. We especially thank Laila Distel and Christine Suchy for excellent technical assistance; Andr{\'e} Reis, Arif Ekici, and Fulvia Ferrazzi at the next-generation sequencing core facility at the Institute of Human Genetics in Erlangen; and Felix Engel for help with the confocal microscope, which was supported by the German Research Foundation (INST 410/91-1 FUGG). C.Z. is supported by grants from the German Research Foundation (ZW184/1-2, ZW184/3-1, and 270949263/GRK2162) and by the Interdisciplinary Center for Clinical Research in Erlangen (E26 and ELAN-Fonds). H.V.E. is a clinical investigator of FWO Vlaanderen. K.{\~O}. and S.P. received support from Estonian Research Council grants PUT355, PRG471, and PUTJD827. M.H.W. is supported by T32GM007748. This study makes use of data generated by the DECIPHER community. Funding for the project was provided by the Wellcome Trust. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. The Broad Center for Mendelian Genomics (UM1 HG008900) is funded by the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute. Please also see Supplementary Acknowledgements. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41436-019-0585-z",

language = "English (US)",

volume = "21",

pages = "2723--2733",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Lippincott Williams and Wilkins",

number = "12",

}

TY - JOUR

T1 - CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

AU - DDD Study

AU - Konrad, Enrico D.H.

AU - Nardini, Niels

AU - Caliebe, Almuth

AU - Nagel, Inga

AU - Young, Dana

AU - Horvath, Gabriella

AU - Santoro, Stephanie L.

AU - Shuss, Christine

AU - Ziegler, Alban

AU - Bonneau, Dominique

AU - Kempers, Marlies

AU - Pfundt, Rolph

AU - Legius, Eric

AU - Bouman, Arjan

AU - Stuurman, Kyra E.

AU - Õunap, Katrin

AU - Pajusalu, Sander

AU - Wojcik, Monica H.

AU - Vasileiou, Georgia

AU - Le Guyader, Gwenaël

AU - Schnelle, Hege M.

AU - Berland, Siren

AU - Zonneveld-Huijssoon, Evelien

AU - Kersten, Simone

AU - Gupta, Aditi

AU - Blackburn, Patrick R.

AU - Ellingson, Marissa S.

AU - Ferber, Matthew J.

AU - Dhamija, Radhika

AU - Klee, Eric W.

AU - McEntagart, Meriel

AU - Lichtenbelt, Klaske D.

AU - Kenney, Amy

AU - Vergano, Samantha A.

AU - Abou Jamra, Rami

AU - Platzer, Konrad

AU - Ella Pierpont, Mary

AU - Khattar, Divya

AU - Hopkin, Robert J.

AU - Martin, Richard J.

AU - Jongmans, Marjolijn C.J.

AU - Chang, Vivian Y.

AU - Martinez-Agosto, Julian A.

AU - Kuismin, Outi

AU - Kurki, Mitja I.

AU - Pietiläinen, Olli

AU - Palotie, Aarno

AU - Maarup, Timothy J.

AU - Johnson, Diana S.

AU - Venborg Pedersen, Katja

N1 - Funding Information: We thank all individuals and families for participating in this study. We especially thank Laila Distel and Christine Suchy for excellent technical assistance; André Reis, Arif Ekici, and Fulvia Ferrazzi at the next-generation sequencing core facility at the Institute of Human Genetics in Erlangen; and Felix Engel for help with the confocal microscope, which was supported by the German Research Foundation (INST 410/91-1 FUGG). C.Z. is supported by grants from the German Research Foundation (ZW184/1-2, ZW184/3-1, and 270949263/GRK2162) and by the Interdisciplinary Center for Clinical Research in Erlangen (E26 and ELAN-Fonds). H.V.E. is a clinical investigator of FWO Vlaanderen. K.Õ. and S.P. received support from Estonian Research Council grants PUT355, PRG471, and PUTJD827. M.H.W. is supported by T32GM007748. This study makes use of data generated by the DECIPHER community. Funding for the project was provided by the Wellcome Trust. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. The Broad Center for Mendelian Genomics (UM1 HG008900) is funded by the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute. Please also see Supplementary Acknowledgements. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individualswith a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39subjects with variants in CTCF. We performedtranscriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impactof Ctcf dosage alteration on nervous systemdevelopment and function. Results: The individuals in our cohort carried 2 deletions, 8 likelygene-disruptive, 2 splice-site, and 20 different missense variants, most of themde novo. Two cases were familial. The associated phenotype was of variableseverity extending from mild developmental delay or normal IQ to severeintellectual disability. Feeding difficulties and behavioral abnormalities werecommon, and variable other findings including growth restriction and cardiacdefects were observed. RNA-sequencing in five individuals identified 3828deregulated genes enriched for known NDD genes and biological processes such astranscriptional regulation. Ctcf dosagealteration in Drosophila resulted in impairedgross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed lightonto the functional role of CTCF by identifying deregulated genes and show thatCtcf alterations result in nervous system defects in Drosophila.

AB - Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individualswith a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39subjects with variants in CTCF. We performedtranscriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impactof Ctcf dosage alteration on nervous systemdevelopment and function. Results: The individuals in our cohort carried 2 deletions, 8 likelygene-disruptive, 2 splice-site, and 20 different missense variants, most of themde novo. Two cases were familial. The associated phenotype was of variableseverity extending from mild developmental delay or normal IQ to severeintellectual disability. Feeding difficulties and behavioral abnormalities werecommon, and variable other findings including growth restriction and cardiacdefects were observed. RNA-sequencing in five individuals identified 3828deregulated genes enriched for known NDD genes and biological processes such astranscriptional regulation. Ctcf dosagealteration in Drosophila resulted in impairedgross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed lightonto the functional role of CTCF by identifying deregulated genes and show thatCtcf alterations result in nervous system defects in Drosophila.

KW - CTCF

KW - Drosophila melanogaster

KW - chromatin organization

KW - intellectual disability

KW - neurodevelopmental disorders

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UR - http://www.scopus.com/inward/citedby.url?scp=85068054841&partnerID=8YFLogxK

U2 - 10.1038/s41436-019-0585-z

DO - 10.1038/s41436-019-0585-z

M3 - Article

C2 - 31239556

AN - SCOPUS:85068054841

SN - 1098-3600

VL - 21

SP - 2723

EP - 2733

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 12

ER -

CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Abstract

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