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      • Record: found
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      Is Open Access

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

      research-article
      , MS 1 , , MS 1 , , MD 2 , , PhD 2 , 3 , , MS 4 , , MD PhD 4 , , MD 5 , , MS 5 , , MD 6 , , MD PhD 6 , , MD PhD 7 , , PhD 7 , , MD PhD 8 , , MD 9 , , MD 9 , , MD PhD 10 , 11 , 12 , , MD PhD 10 , 11 , 13 , , MD 12 , 14 , , PhD 1 , , MD PhD 15 , , MD 16 , , MD 16 , , MD PhD 17 , , MS 7 , , PhD 18 , , PhD 19 , , MS 19 , , PhD 19 , , MBBS 20 , , PhD 18 , , MD 21 , , MD 22 , , MS 23 , , MD 23 , , MD 24 , , MD 24 , , MD PhD 25 , , MD 26 , , MD 26 , , MD 27 , , MD PhD 7 , , MD MS 28 , 29 , , MD PhD 30 , 31 , , MD 32 , 33 , 34 , 35 , , PhD 32 , 36 , 37 , , PhD 37 , 38 , , MD PhD 32 , 36 , 37 , 39 , 40 , , MD 41 , , BM MD 42 , , MD PhD 43 , , MD 44 , , MD 45 , , MBChB DM 46 , , MBBS PhD 46 , , MB, ChB 47 , , MD 47 , , MD 22 , , MD 48 , , MS 48 , DDD Study 49 , , PhD 50 , , PhD 1 , , MD PhD 51 , , MD PhD 1 ,
      Genetics in Medicine
      Nature Publishing Group US
      CTCF, neurodevelopmental disorders, Drosophila melanogaster, intellectual disability, chromatin organization

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          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 of CTCF-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.

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          Most cited references25

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          Gene Ontology: tool for the unification of biology

          Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
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            Is Open Access

            Heavy-tailed prior distributions for sequence count data: removing the noise and preserving large differences

            Abstract Motivation In RNA-seq differential expression analysis, investigators aim to detect those genes with changes in expression level across conditions, despite technical and biological variability in the observations. A common task is to accurately estimate the effect size, often in terms of a logarithmic fold change (LFC). Results When the read counts are low or highly variable, the maximum likelihood estimates for the LFCs has high variance, leading to large estimates not representative of true differences, and poor ranking of genes by effect size. One approach is to introduce filtering thresholds and pseudocounts to exclude or moderate estimated LFCs. Filtering may result in a loss of genes from the analysis with true differences in expression, while pseudocounts provide a limited solution that must be adapted per dataset. Here, we propose the use of a heavy-tailed Cauchy prior distribution for effect sizes, which avoids the use of filter thresholds or pseudocounts. The proposed method, Approximate Posterior Estimation for generalized linear model, apeglm, has lower bias than previously proposed shrinkage estimators, while still reducing variance for those genes with little information for statistical inference. Availability and implementation The apeglm package is available as an R/Bioconductor package at https://bioconductor.org/packages/apeglm, and the methods can be called from within the DESeq2 software. Supplementary information Supplementary data are available at Bioinformatics online.
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              Use of Exome Sequencing for Infants in Intensive Care Units

              While congenital malformations and genetic diseases are a leading cause of early infant death, to our knowledge, the contribution of single-gene disorders in this group is undetermined.
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                Author and article information

                Contributors
                christiane.zweier@uk-erlangen.de
                Journal
                Genet Med
                Genet. Med
                Genetics in Medicine
                Nature Publishing Group US (New York )
                1098-3600
                1530-0366
                26 June 2019
                26 June 2019
                2019
                : 21
                : 12
                : 2723-2733
                Affiliations
                [1 ]ISNI 0000 0001 2107 3311, GRID grid.5330.5, Institute of Human Genetics, , Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), ; Erlangen, Germany
                [2 ]ISNI 0000 0001 2153 9986, GRID grid.9764.c, Institute of Human Genetics, , Universitätsklinikum Schleswig Holstein Campus Kiel and Christian-Albrechts-Universität, ; Kiel, Germany
                [3 ]ISNI 0000 0004 0646 2097, GRID grid.412468.d, Institute of Experimental and Clinical Pharmacology, , University Hospital Schleswig-Holstein, Campus Kiel, ; Kiel, Germany
                [4 ]ISNI 0000 0001 0684 7796, GRID grid.412541.7, Adult Metabolic Diseases Clinic, , Vancouver General Hospital, ; Vancouver, BC Canada
                [5 ]ISNI 0000 0004 0392 3476, GRID grid.240344.5, Division of Molecular and Human Genetics, , Nationwide Children’s Hospital, ; Columbus, OH USA
                [6 ]ISNI 0000 0004 0472 0283, GRID grid.411147.6, Département de Biochimie et Génétique, , CHU Angers et Mitolab INSERM 1083—CNRS 6015, ; Angers, France
                [7 ]GRID grid.461760.2, 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 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Clinical Genetics, , Erasmus MC, University Medical Center Rotterdam, ; Rotterdam, The Netherlands
                [10 ]ISNI 0000 0001 0585 7044, GRID grid.412269.a, Department of Clinical Genetics, , United Laboratories, Tartu University Hospital, ; Tartu, Estonia
                [11 ]ISNI 0000 0001 0943 7661, GRID grid.10939.32, Department of Clinical Genetics, , Institute of Clinical Medicine, University of Tartu, ; Tartu, Estonia
                [12 ]GRID grid.66859.34, The Broad Institute of MIT and Harvard, ; Cambridge, MA USA
                [13 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Genetics, , Yale University School of Medicine, ; New Haven, CT USA
                [14 ]ISNI 0000 0004 0378 8438, GRID grid.2515.3, Divisions of Genetics and Genomics and Newborn Medicine, Department of Pediatrics, , Boston Children’s Hospital, ; Boston, MA USA
                [15 ]ISNI 0000 0000 9336 4276, GRID grid.411162.1, Service de Génétique Clinique, CHU de Poitiers, ; Poitiers, France
                [16 ]ISNI 0000 0000 9753 1393, GRID grid.412008.f, Department of Medical Genetics, , Haukeland University Hospital, ; Bergen, Norway
                [17 ]Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
                [18 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Center for Individualized Medicine, , Mayo Clinic, ; Rochester, MN USA
                [19 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Department of Laboratory Medicine and Pathology, , Mayo Clinic, ; Rochester, MN USA
                [20 ]ISNI 0000 0000 8875 6339, GRID grid.417468.8, Department of Clinical Genomics, , Mayo Clinic, ; Scottsdale, AZ USA
                [21 ]ISNI 0000000121901201, GRID grid.83440.3b, South West Thames Regional Genetics Centre, , St. George’s Healthcare NHS Trust, St. George’s, University of London, ; London, UK
                [22 ]ISNI 0000000090126352, GRID grid.7692.a, Department of Genetics, , University Medical Center Utrecht, ; Utrecht, The Netherlands
                [23 ]ISNI 0000 0004 0426 1259, GRID grid.414165.3, Division of Medical Genetics and Metabolism, , Children’s Hospital of The King’s Daughters, ; Norfolk, VA USA
                [24 ]ISNI 0000 0001 2230 9752, GRID grid.9647.c, Institute of Human Genetics, , University of Leipzig Medical Center, ; Leipzig, Germany
                [25 ]ISNI 0000000419368657, GRID grid.17635.36, Department of Pediatrics, Division of Genetics and Metabolism, , University of Minnesota, ; Minneapolis, MN USA
                [26 ]ISNI 0000 0000 9025 8099, GRID grid.239573.9, Division of Human Genetics, , Cincinnati Children’s Hospital Medical Center, ; Cincinnati, OH USA
                [27 ]ISNI 0000 0004 0444 2244, GRID grid.420004.2, The Newcastle upon Tyne Hospitals NHS Foundation Trust, ; Newcastle upon Tyne, UK
                [28 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Division of Pediatric Hematology-Oncology, Department of Pediatrics, , David Geffen School of Medicine, ; Los Angeles, CA USA
                [29 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Jonsson Comprehensive Cancer Center, , University of California, ; Los Angeles, CA USA
                [30 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Division of Medical Genetics, Department of Pediatrics, , David Geffen School of Medicine, University of California, ; Los Angeles, CA USA
                [31 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Department of Human Genetics, , David Geffen School of Medicine, University of California, ; Los Angeles, CA USA
                [32 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Institute for Molecular Medicine Finland, , University of Helsinki, ; Helsinki, Finland
                [33 ]ISNI 0000 0001 0941 4873, GRID grid.10858.34, PEDEGO Research Unit, , University of Oulu, ; Oulu, Finland
                [34 ]Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
                [35 ]ISNI 0000 0004 4685 4917, GRID grid.412326.0, Department of Clinical Genetics, , Oulu University Hospital, ; Oulu, Finland
                [36 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Psychiatric & Neurodevelopmental Genetics Unit, , Massachusetts General Hospital, ; Boston, MA USA
                [37 ]GRID grid.66859.34, The Stanley Center for Psychiatric Research, , The Broad Institute of MIT and Harvard, ; Cambridge, MA USA
                [38 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Stem Cell and Regenerative Biology, , University of Harvard, ; Cambridge, MA USA
                [39 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Analytic and Translational Genetics Unit, Department of Medicine, , Massachusetts General Hospital, ; Boston, MA USA
                [40 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Department of Neurology, , Massachusetts General Hospital, ; Boston, MA USA
                [41 ]ISNI 0000 0004 0445 1191, GRID grid.414895.5, Department of Genetics, , Kaiser Permanente, ; Los Angeles, CA USA
                [42 ]ISNI 0000 0004 0641 6082, GRID grid.413991.7, Sheffield Children’s Hospital, ; Sheffield, UK
                [43 ]ISNI 0000 0004 0512 5013, GRID grid.7143.1, Department of Clinical Genetics, , Odense University Hospital, ; Odense, Denmark
                [44 ]ISNI 0000 0004 0512 5013, GRID grid.7143.1, Department of Pediatrics, , Odense University Hospital, ; Odense, Denmark
                [45 ]ISNI 0000 0001 0768 2743, GRID grid.7886.1, University College Dublin and Temple Street Children’s Hospital, ; Dublin, Ireland
                [46 ]ISNI 0000 0004 0426 1312, GRID grid.413818.7, Yorkshire Regional Genetics Service, , Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, ; Leeds, UK
                [47 ]ISNI 0000 0004 0398 9627, GRID grid.416568.8, North West Thames Regional Genetics Service, , Northwick Park Hospital, ; Harrow, UK
                [48 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Division of Genetics and Genomic Medicine, Department of Pediatrics, , Washington University School of Medicine, ; St. Louis, MO USA
                [49 ]Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
                [50 ]ISNI 0000 0001 2107 3311, GRID grid.5330.5, Institute of Biochemistry, , Emil-Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, ; Erlangen, Germany
                [51 ]Center for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium
                Author information
                http://orcid.org/0000-0003-0209-1156
                http://orcid.org/0000-0002-4594-6364
                http://orcid.org/0000-0002-5435-0781
                http://orcid.org/0000-0002-8162-5031
                http://orcid.org/0000-0002-8048-6682
                http://orcid.org/0000-0002-9503-6297
                http://orcid.org/0000-0002-0251-5564
                http://orcid.org/0000-0003-3647-8148
                http://orcid.org/0000-0003-0658-1275
                http://orcid.org/0000-0003-1710-8854
                http://orcid.org/0000-0001-8052-2586
                http://orcid.org/0000-0002-9943-5236
                http://orcid.org/0000-0003-0770-5516
                http://orcid.org/0000-0002-4312-413X
                http://orcid.org/0000-0001-5644-045X
                http://orcid.org/0000-0001-9166-6593
                http://orcid.org/0000-0001-8002-2020
                Article
                585
                10.1038/s41436-019-0585-z
                6892744
                31239556
                4fad31dd-9a34-4dc9-a83f-20faf4c53612
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. If you remix, transform, or build upon this article or a part thereof, you must distribute your contributions under the same license as the original. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/.

                History
                : 3 April 2019
                : 6 June 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: ZW184/1-2
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: ZW184/3-1
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: 270949263/GRK2162
                Award Recipient :
                Funded by: IZKF, Medizinische Fakultät, Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
                Award ID: E26
                Award Recipient :
                Funded by: FWO Vlaanderen
                Award ID: 0000
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100004440, Wellcome Trust;
                Award ID: WT098051
                Funded by: Health Innovation Challenge Fund
                Award ID: HICF-1009-003
                Funded by: FundRef http://dx.doi.org/10.13039/100000051, National Human Genome Research Institute;
                Award ID: UM1 HG008900
                Funded by: Estonian Research Council
                Award ID: PUT355
                Funded by: Estonian Research Council
                Award ID: PRG471
                Funded by: Estonian Research Council
                Award ID: PUTJD827
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: T32GM007748
                Award Recipient :
                Funded by: ELAN-Fonds, FAU Erlangen-Nürnberg
                Award ID: 0000
                Award Recipient :
                Categories
                Article
                Custom metadata
                © American College of Medical Genetics and Genomics 2019

                Genetics
                ctcf,neurodevelopmental disorders,drosophila melanogaster,intellectual disability,chromatin organization

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