2. Academic Validation
  3. TAF1 Variants Are Associated with Dysmorphic Features, Intellectual Disability, and Neurological Manifestations

TAF1 Variants Are Associated with Dysmorphic Features, Intellectual Disability, and Neurological Manifestations

  • Am J Hum Genet. 2015 Dec 3;97(6):922-32. doi: 10.1016/j.ajhg.2015.11.005.
Jason A O'Rawe 1,  Yiyang Wu 1,  Max J Dörfel 2,  Alan F Rope 3,  P Y Billie Au 4,  Jillian S Parboosingh 4,  Sungjin Moon 5,  Maria Kousi 5,  Konstantina Kosma 6,  Christopher S Smith 4,  Maria Tzetis 6,  Jane L Schuette 7,  Robert B Hufnagel 8,  Carlos E Prada 9,  Francisco Martinez 10,  Carmen Orellana 10,  Jonathan Crain 2,  Alfonso Caro-Llopis 10,  Silvestre Oltra 10,  Sandra Monfort 10,  Laura T Jiménez-Barrón 11,  Jeffrey Swensen 12,  Sara Ellingwood 13,  Rosemarie Smith 14,  Han Fang 2,  Sandra Ospina 15,  Sander Stegmann 16,  Nicolette Den Hollander 17,  David Mittelman 18,  Gareth Highnam 18,  Reid Robison 19,  Edward Yang 20,  Laurence Faivre 21,  Agathe Roubertie 22,  Jean-Baptiste Rivière 23,  Kristin G Monaghan 24,  Kai Wang 25,  Erica E Davis 5,  Nicholas Katsanis 5,  Vera M Kalscheuer 26,  Edith H Wang 27,  Kay Metcalfe 28,  Tjitske Kleefstra 29,  A Micheil Innes 4,  Sophia Kitsiou-Tzeli 30,  Monica Rosello 10,  Catherine E Keegan 7,  Gholson J Lyon 31
Affiliations

Affiliations

  • 1 Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Graduate Program in Genetics, Stony Brook University, Stony Brook, NY 11794, USA.
  • 2 Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
  • 3 Department of Medical Genetics, Northwest Kaiser Permanente, Portland, OR 97227, USA.
  • 4 Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T3B 6A8, Canada.
  • 5 Center for Human Disease Modeling, Duke University, Durham, NC 27708, USA.
  • 6 Department of Medical Genetics, Medical School, University of Athens, Athens 11527, Greece; Research Institute for the Study of Genetic and Malignant Disorders in Childhood, Aghia Sophia, Children's Hospital, Athens 11527, Greece.
  • 7 Department of Pediatrics, Division of Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
  • 8 Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA; Unit on Pediatric, Developmental, and Genetic Ophthalmology, Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD 20892, USA.
  • 9 Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA; Centro de Medicina Genómica y Metabolismo, Fundación Cardiovascular de Colombia, Bucaramanga, Santander 681004, Colombia.
  • 10 Unidad de Genetica, Hospital Universitario y Politecnico La Fe, Valencia 46026, Spain.
  • 11 Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Centro de Ciencias Genomicas, Universidad Nacional Autonoma de México, Cuernavaca, Morelos 62210, Mexico.
  • 12 Caris Life Sciences, Phoenix, AZ 85040, USA.
  • 13 Division of Genetics, Pediatric Specialty Care, Maine Medical Partners, ME 04102, USA.
  • 14 Department of Pediatrics, Division of Genetics, Barbara Bush Children's Hospital, Maine Medical Center, Portland, ME 04102, USA.
  • 15 Fundacion Cardioinfantil and Universidad del Rosario, Bogota 681004, Colombia.
  • 16 Deptartment of Clinical Genetics, 6202 AZ Maastricht, the Netherlands.
  • 17 Department of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
  • 18 Gene by Gene Ltd., Houston, TX 77008, USA.
  • 19 Utah Foundation for Biomedical Research, Salt Lake City, UT 84107, USA; Tute Genomics, 150 South 100 West Street, Provo, UT 84601, USA.
  • 20 Department of Radiology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 21 Génétique des Anomalies du Développement EA4271, Université Bourgogne Franche-Comté, 21000 Dijon, France; Centre de Génétique, Centre de Référence Maladies Rares "Anomalies du Développement et Syndromes Malformatifs," Centre Hospitalier Universitaire de Dijon, 21000 Dijon, France.
  • 22 Institut des Neurosciences de Montpellier, Université de Montpellier, BP 74103, 34950 Montpellier Cedex 5, France; Service de Neuropédiatrie, Centre Hospitalier Universitaire Gui de Chauliac, 34000 Montpellier, France.
  • 23 Génétique des Anomalies du Développement EA4271, Université Bourgogne Franche-Comté, 21000 Dijon, France.
  • 24 GeneDx, Gaithersburg, MD 20877, USA.
  • 25 Zilkha Neurogenetic Institute, Department of Psychiatry and Preventive Medicine, University of Southern California, Los Angeles, CA 90089, USA.
  • 26 Research Group Development and Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
  • 27 Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
  • 28 Clinical Genetics Service, Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Oxford Road, Manchester M13 9WL, UK.
  • 29 Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
  • 30 Department of Medical Genetics, Medical School, University of Athens, Athens 11527, Greece.
  • 31 Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Graduate Program in Genetics, Stony Brook University, Stony Brook, NY 11794, USA; Utah Foundation for Biomedical Research, Salt Lake City, UT 84107, USA. Electronic address: gholsonjlyon@gmail.com.
PMID: 26637982 DOI: 10.1016/j.ajhg.2015.11.005
Abstract

We describe an X-linked genetic syndrome associated with mutations in TAF1 and manifesting with global developmental delay, intellectual disability (ID), characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male individuals. Simultaneous studies using diverse strategies led to the identification of nine families with overlapping clinical presentations and affected by de novo or maternally inherited single-nucleotide changes. Two additional families harboring large duplications involving TAF1 were also found to share phenotypic overlap with the probands harboring single-nucleotide changes, but they also demonstrated a severe neurodegeneration phenotype. Functional analysis with RNA-seq for one of the families suggested that the phenotype is associated with downregulation of a set of genes notably enriched with genes regulated by E-box proteins. In addition, knockdown and mutant studies of this gene in zebrafish have shown a quantifiable, albeit small, effect on a neuronal phenotype. Our results suggest that mutations in TAF1 play a critical role in the development of this X-linked ID syndrome.

Keywords

TAF1; abnormal gait; developmental delay; dystonia; facial dysmorphology; intellectual disability; intergluteal crease; neurologic features; transcription.

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