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

doi:10.1038/s41436-019-0585-z

. 2019 Dec;21(12):2723-2733.

doi: 10.1038/s41436-019-0585-z. Epub 2019 Jun 26.

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

Enrico D H Konrad¹, Niels Nardini¹, Almuth Caliebe², Inga Nagel^{2

3}, Dana Young⁴, Gabriella Horvath⁴, Stephanie L Santoro⁵, Christine Shuss⁵, Alban Ziegler⁶, Dominique Bonneau⁶, Marlies Kempers⁷, Rolph Pfundt⁷, Eric Legius⁸, Arjan Bouman⁹, Kyra E Stuurman⁹, Katrin Õunap^{10

11

12}, Sander Pajusalu^{10

11

13}, Monica H Wojcik^{12

14}, Georgia Vasileiou¹, Gwenaël Le Guyader¹⁵, Hege M Schnelle¹⁶, Siren Berland¹⁶, Evelien Zonneveld-Huijssoon¹⁷, Simone Kersten⁷, Aditi Gupta¹⁸, Patrick R Blackburn¹⁹, Marissa S Ellingson¹⁹, Matthew J Ferber¹⁹, Radhika Dhamija²⁰, Eric W Klee¹⁸, Meriel McEntagart²¹, Klaske D Lichtenbelt²², Amy Kenney²³, Samantha A Vergano²³, Rami Abou Jamra²⁴, Konrad Platzer²⁴, Mary Ella Pierpont²⁵, Divya Khattar²⁶, Robert J Hopkin²⁶, Richard J Martin²⁷, Marjolijn C J Jongmans⁷, Vivian Y Chang^{28

29}, Julian A Martinez-Agosto^{30

31}, Outi Kuismin^{32

33

34

35}, Mitja I Kurki^{32

36

37}, Olli Pietiläinen^{37

38}, Aarno Palotie^{32

36

37

39

40}, Timothy J Maarup⁴¹, Diana S Johnson⁴², Katja Venborg Pedersen⁴³, Lone W Laulund⁴⁴, Sally A Lynch⁴⁵, Moira Blyth⁴⁶, Katrina Prescott⁴⁶, Natalie Canham⁴⁷, Rita Ibitoye⁴⁷, Eva H Brilstra²², Marwan Shinawi⁴⁸, Emily Fassi⁴⁸; DDD Study; Heinrich Sticht⁴⁹, Anne Gregor¹, Hilde Van Esch⁵⁰, Christiane Zweier⁵¹

Affiliations

¹ Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
² Institute of Human Genetics, Universitätsklinikum Schleswig Holstein Campus Kiel and Christian-Albrechts-Universität, Kiel, Germany.
³ Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
⁴ Adult Metabolic Diseases Clinic, Vancouver General Hospital, Vancouver, BC, Canada.
⁵ Division of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH, USA.
⁶ Département de Biochimie et Génétique, CHU Angers et Mitolab INSERM 1083-CNRS 6015, Angers, France.
⁷ Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
⁸ Department of Human Genetics, KU Leuven and Center for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
⁹ Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁰ Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
¹¹ Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
¹² The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹³ Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
¹⁴ Divisions of Genetics and Genomics and Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
¹⁵ Service de Génétique Clinique, CHU de Poitiers, Poitiers, France.
¹⁶ Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
¹⁷ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹⁸ Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
¹⁹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
²⁰ Department of Clinical Genomics, Mayo Clinic, Scottsdale, AZ, USA.
²¹ South West Thames Regional Genetics Centre, St. George's Healthcare NHS Trust, St. George's, University of London, London, UK.
²² Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
²³ Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA, USA.
²⁴ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
²⁵ Department of Pediatrics, Division of Genetics and Metabolism, University of Minnesota, Minneapolis, MN, USA.
²⁶ Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
²⁷ The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
²⁸ Division of Pediatric Hematology-Oncology, Department of Pediatrics, David Geffen School of Medicine, Los Angeles, CA, USA.
²⁹ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
³⁰ Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
³¹ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
³² Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
³³ PEDEGO Research Unit, University of Oulu, Oulu, Finland.
³⁴ Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland.
³⁵ Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland.
³⁶ Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
³⁷ The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³⁸ Department of Stem Cell and Regenerative Biology, University of Harvard, Cambridge, MA, USA.
³⁹ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴⁰ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
⁴¹ Department of Genetics, Kaiser Permanente, Los Angeles, CA, USA.
⁴² Sheffield Children's Hospital, Sheffield, UK.
⁴³ Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
⁴⁴ Department of Pediatrics, Odense University Hospital, Odense, Denmark.
⁴⁵ University College Dublin and Temple Street Children's Hospital, Dublin, Ireland.
⁴⁶ Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
⁴⁷ North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, UK.
⁴⁸ Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
⁴⁹ Institute of Biochemistry, Emil-Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
⁵⁰ Center for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
⁵¹ Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. christiane.zweier@uk-erlangen.de.

PMID: 31239556
PMCID: PMC6892744
DOI: 10.1038/s41436-019-0585-z

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

Enrico D H Konrad et al. Genet Med. 2019 Dec.

. 2019 Dec;21(12):2723-2733.

doi: 10.1038/s41436-019-0585-z. Epub 2019 Jun 26.

Authors

Affiliations

¹ Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
² Institute of Human Genetics, Universitätsklinikum Schleswig Holstein Campus Kiel and Christian-Albrechts-Universität, Kiel, Germany.
³ Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
⁴ Adult Metabolic Diseases Clinic, Vancouver General Hospital, Vancouver, BC, Canada.
⁵ Division of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH, USA.
⁶ Département de Biochimie et Génétique, CHU Angers et Mitolab INSERM 1083-CNRS 6015, Angers, France.
⁷ Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
⁸ Department of Human Genetics, KU Leuven and Center for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
⁹ Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁰ Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
¹¹ Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
¹² The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹³ Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
¹⁴ Divisions of Genetics and Genomics and Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
¹⁵ Service de Génétique Clinique, CHU de Poitiers, Poitiers, France.
¹⁶ Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
¹⁷ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹⁸ Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
¹⁹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
²⁰ Department of Clinical Genomics, Mayo Clinic, Scottsdale, AZ, USA.
²¹ South West Thames Regional Genetics Centre, St. George's Healthcare NHS Trust, St. George's, University of London, London, UK.
²² Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
²³ Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA, USA.
²⁴ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
²⁵ Department of Pediatrics, Division of Genetics and Metabolism, University of Minnesota, Minneapolis, MN, USA.
²⁶ Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
²⁷ The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
²⁸ Division of Pediatric Hematology-Oncology, Department of Pediatrics, David Geffen School of Medicine, Los Angeles, CA, USA.
²⁹ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
³⁰ Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
³¹ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
³² Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
³³ PEDEGO Research Unit, University of Oulu, Oulu, Finland.
³⁴ Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland.
³⁵ Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland.
³⁶ Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
³⁷ The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³⁸ Department of Stem Cell and Regenerative Biology, University of Harvard, Cambridge, MA, USA.
³⁹ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴⁰ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
⁴¹ Department of Genetics, Kaiser Permanente, Los Angeles, CA, USA.
⁴² Sheffield Children's Hospital, Sheffield, UK.
⁴³ Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
⁴⁴ Department of Pediatrics, Odense University Hospital, Odense, Denmark.
⁴⁵ University College Dublin and Temple Street Children's Hospital, Dublin, Ireland.
⁴⁶ Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
⁴⁷ North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, UK.
⁴⁸ Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
⁴⁹ Institute of Biochemistry, Emil-Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
⁵⁰ Center for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
⁵¹ Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. christiane.zweier@uk-erlangen.de.

PMID: 31239556
PMCID: PMC6892744
DOI: 10.1038/s41436-019-0585-z

Abstract

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD).

Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function.

Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits.

Conclusion: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

Keywords: CTCF; Drosophila melanogaster; chromatin organization; intellectual disability; neurodevelopmental disorders.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

**Fig. 1**
**Variants identified in*CTCF***. a Schematic drawing of the *CTCF* gene with known and novel variants. Noncoding exons are displayed in light gray, coding exons in medium gray, and exons encoding zinc fingers in dark gray. b Schematic drawing of the CTCF protein. Missense or in-frame variants are displayed above and likely gene-disruptive variants below the scheme. Nonbold variants and p.(Arg567Trp) were published previously with or *without clinical details.^{–, –} Underlined variants are recurrent. All identified pathogenic or likely pathogenic in-frame or missense variants affect one of the 11 zinc finger domains.

**Fig. 2**
**Facial gestalt of individuals with pathogenic variants in*CTCF***. Note minor facial dysmorphism such as a long face (e.g., I5, I8, I11, I27), a prominent forehead (e.g., I4, I8, I18, I33, I35) or a bulbous nasal tip and long palpebral fissures in several individuals, but no overall distinct, recognizable facial gestalt.

**Fig. 3**
**Transcriptome analysis in*CTCF*-deficient individuals.**a Heatmap displaying the 3828 differentially expressed genes between five affected individuals and eight healthy controls and depicting the expression similarity between individuals with corrected p value <0.01; 2161 genes were downregulated and 1667 genes were upregulated in the affected individuals. Individuals are clustered by Euclidean distance, and genes are sorted by adjusted p value. Blue, downregulated; red, upregulated.b, c Gene Ontology (GO) term analysis on b downregulated and c upregulated genes depicting the top five GO terms for biological processes *FDR* false discovery rate.

**Fig. 4**
**Impact of*Ctcf*dosage alteration on fly gross neurological functioning and learning and memory.**a–c Flies with knockdown of *Ctcf* in a motoneurons and b all neurons but not in c glia showed significant locomotor impairment in the climbing assay. Pan-neuronal overexpression b had no effect, but c glial and a motoneuronal driven overexpression ofCtcf resulted in significant locomotor impairment. The numbers below the columns represent the samples in groups of ten flies tested per genotype. d In the courtship conditioning paradigm, the hypomorphic *Ctcf* mutant line showed highly significant impairment of learning (L) and short-term memory (STM) and significant impairment of long-term memory (LTM). e In accordance, mushroom body–driven (UAS-*Dcr-2*;*247*-GAL4) knockdown of *Ctcf* resulted in significantly reduced short-term memory (STM). Similar tendencies were observed for L and LTM, but not reaching significance. f Overexpression of *Ctcf* in the mushroom body did not result in a significant effect on L and STM, but in a significant impairment of long-term memory. Graphs display mean values of the number of animals indicated below the columns per genotype from at least three independent test days. Differences between learning indexes of control and mutant flies were statistically compared by a randomization test with 10,000 bootstrap replicates with a custom R script. Error bars depict SEM. Asterisks indicate statistical significance (p value: *≤0.05, **≤0.01, ***≤0.001).

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References

1. Gerasimova TI, Byrd K, Corces VG. A chromatin insulator determines the nuclear localization of DNA. Mol Cell. 2000;6:1025–1035. doi: 10.1016/S1097-2765(00)00101-5. - DOI - PubMed
1. Ji X, Dadon DB, Powell BE, et al. 3D chromosome regulatory landscape of human pluripotent cells. Cell Stem Cell. 2016;18:262–275. doi: 10.1016/j.stem.2015.11.007. - DOI - PMC - PubMed
1. Bell AC, Felsenfeld G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature. 2000;405:482–485. doi: 10.1038/35013100. - DOI - PubMed
1. Chao W, Huynh KD, Spencer RJ, Davidow LS, Lee JT. CTCF, a candidate trans-acting factor for X-inactivation choice. Science. 2002;295:345–347. doi: 10.1126/science.1065982. - DOI - PubMed
1. Klenova EM, Nicolas RH, Paterson HF, et al. CTCF, a conserved nuclear factor required for optimal transcriptional activity of the chicken c-myc gene, is an 11-Zn-finger protein differentially expressed in multiple forms. Mol Cell Biol. 1993;13:7612–7624. doi: 10.1128/MCB.13.12.7612. - DOI - PMC - PubMed

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[1] Gerasimova TI, Byrd K, Corces VG. A chromatin insulator determines the nuclear localization of DNA. Mol Cell. 2000;6:1025–1035. doi: 10.1016/S1097-2765(00)00101-5. - DOI - PubMed

[2] Gerasimova TI, Byrd K, Corces VG. A chromatin insulator determines the nuclear localization of DNA. Mol Cell. 2000;6:1025–1035. doi: 10.1016/S1097-2765(00)00101-5. - DOI - PubMed

[3] Ji X, Dadon DB, Powell BE, et al. 3D chromosome regulatory landscape of human pluripotent cells. Cell Stem Cell. 2016;18:262–275. doi: 10.1016/j.stem.2015.11.007. - DOI - PMC - PubMed

[4] Ji X, Dadon DB, Powell BE, et al. 3D chromosome regulatory landscape of human pluripotent cells. Cell Stem Cell. 2016;18:262–275. doi: 10.1016/j.stem.2015.11.007. - DOI - PMC - PubMed

[5] Bell AC, Felsenfeld G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature. 2000;405:482–485. doi: 10.1038/35013100. - DOI - PubMed

[6] Bell AC, Felsenfeld G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature. 2000;405:482–485. doi: 10.1038/35013100. - DOI - PubMed

[7] Chao W, Huynh KD, Spencer RJ, Davidow LS, Lee JT. CTCF, a candidate trans-acting factor for X-inactivation choice. Science. 2002;295:345–347. doi: 10.1126/science.1065982. - DOI - PubMed

[8] Chao W, Huynh KD, Spencer RJ, Davidow LS, Lee JT. CTCF, a candidate trans-acting factor for X-inactivation choice. Science. 2002;295:345–347. doi: 10.1126/science.1065982. - DOI - PubMed

[9] Klenova EM, Nicolas RH, Paterson HF, et al. CTCF, a conserved nuclear factor required for optimal transcriptional activity of the chicken c-myc gene, is an 11-Zn-finger protein differentially expressed in multiple forms. Mol Cell Biol. 1993;13:7612–7624. doi: 10.1128/MCB.13.12.7612. - DOI - PMC - PubMed

[10] Klenova EM, Nicolas RH, Paterson HF, et al. CTCF, a conserved nuclear factor required for optimal transcriptional activity of the chicken c-myc gene, is an 11-Zn-finger protein differentially expressed in multiple forms. Mol Cell Biol. 1993;13:7612–7624. doi: 10.1128/MCB.13.12.7612. - DOI - PMC - PubMed

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

Affiliations

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

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