title: TAF1 Variants Are Associated with Dysmorphic Features, Intellectual Disability, and Neurological Manifestations.
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.
authors.affiliation: 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.
authors.forename: Jason A
authors.initials: JA
authors.lastname: O'Rawe
authors.affiliation: 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.
authors.forename: Yiyang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Max J
authors.initials: MJ
authors.lastname: Dörfel
authors.affiliation: Department of Medical Genetics, Northwest Kaiser Permanente, Portland, OR 97227, USA.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Rope
authors.affiliation: Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T3B 6A8, Canada.
authors.forename: P Y Billie
authors.initials: PY
authors.lastname: Au
authors.affiliation: Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T3B 6A8, Canada.
authors.forename: Jillian S
authors.initials: JS
authors.lastname: Parboosingh
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, NC 27708, USA.
authors.forename: Sungjin
authors.initials: S
authors.lastname: Moon
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, NC 27708, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Kousi
authors.affiliation: 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.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Kosma
authors.affiliation: Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T3B 6A8, Canada.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Smith
authors.affiliation: 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.
authors.forename: Maria
authors.initials: M
authors.lastname: Tzetis
authors.affiliation: 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.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Schuette
authors.affiliation: 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.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Hufnagel
authors.affiliation: 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.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Prada
authors.affiliation: Unidad de Genetica, Hospital Universitario y Politecnico La Fe, Valencia 46026, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Martinez
authors.affiliation: Unidad de Genetica, Hospital Universitario y Politecnico La Fe, Valencia 46026, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Orellana
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Crain
authors.affiliation: Unidad de Genetica, Hospital Universitario y Politecnico La Fe, Valencia 46026, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Caro-Llopis
authors.affiliation: Unidad de Genetica, Hospital Universitario y Politecnico La Fe, Valencia 46026, Spain.
authors.forename: Silvestre
authors.initials: S
authors.lastname: Oltra
authors.affiliation: Unidad de Genetica, Hospital Universitario y Politecnico La Fe, Valencia 46026, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Monfort
authors.affiliation: 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.
authors.forename: Laura T
authors.initials: LT
authors.lastname: Jiménez-Barrón
authors.affiliation: Caris Life Sciences, Phoenix, AZ 85040, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Swensen
authors.affiliation: Division of Genetics, Pediatric Specialty Care, Maine Medical Partners, ME 04102, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Ellingwood
authors.affiliation: Department of Pediatrics, Division of Genetics, Barbara Bush Children's Hospital, Maine Medical Center, Portland, ME 04102, USA.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Smith
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Fang
authors.affiliation: Fundacion Cardioinfantil and Universidad del Rosario, Bogota 681004, Colombia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ospina
authors.affiliation: Deptartment of Clinical Genetics, 6202 AZ Maastricht, the Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Stegmann
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
authors.forename: Nicolette
authors.initials: N
authors.lastname: Den Hollander
authors.affiliation: Gene by Gene Ltd., Houston, TX 77008, USA.
authors.forename: David
authors.initials: D
authors.lastname: Mittelman
authors.affiliation: Gene by Gene Ltd., Houston, TX 77008, USA.
authors.forename: Gareth
authors.initials: G
authors.lastname: Highnam
authors.affiliation: Utah Foundation for Biomedical Research, Salt Lake City, UT 84107, USA; Tute Genomics, 150 South 100 West Street, Provo, UT 84601, USA.
authors.forename: Reid
authors.initials: R
authors.lastname: Robison
authors.affiliation: Department of Radiology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.affiliation: 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.
authors.forename: Agathe
authors.initials: A
authors.lastname: Roubertie
authors.affiliation: Génétique des Anomalies du Développement EA4271, Université Bourgogne Franche-Comté, 21000 Dijon, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Rivière
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Monaghan
authors.affiliation: Zilkha Neurogenetic Institute, Department of Psychiatry and Preventive Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, NC 27708, USA.
authors.forename: Erica E
authors.initials: EE
authors.lastname: Davis
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, NC 27708, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: Research Group Development and Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Vera M
authors.initials: VM
authors.lastname: Kalscheuer
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Edith H
authors.initials: EH
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Kay
authors.initials: K
authors.lastname: Metcalfe
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T3B 6A8, Canada.
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.affiliation: Department of Medical Genetics, Medical School, University of Athens, Athens 11527, Greece.
authors.forename: Sophia
authors.initials: S
authors.lastname: Kitsiou-Tzeli
authors.affiliation: Unidad de Genetica, Hospital Universitario y Politecnico La Fe, Valencia 46026, Spain.
authors.forename: Monica
authors.initials: M
authors.lastname: Rosello
authors.affiliation: 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.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Keegan
authors.affiliation: 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.
authors.forename: Gholson J
authors.initials: GJ
authors.lastname: Lyon
mesh_terms: D000293:Adolescent; D000818:Animals; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D024721:E-Box Elements; D019066:Facies; D005190:Family; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D040582:Inheritance Patterns; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D015398:Signal Transduction; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics* / Q000378:metabolism; D035362:Transcription Factor TFIID / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D015027:Zebrafish
chemical_list: D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D051548:Histone Acetyltransferases; C069001:TATA-binding protein associated factor 250 kDa
keywords: TAF1; abnormal gait; developmental delay; dystonia; facial dysmorphology; intellectual disability; intergluteal crease; neurologic features; transcription