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Hum Mutat. 2019 Oct 23. doi: 10.1002/humu.23936. [Epub ahead of print]

Missense variants in TAF1 and developmental phenotypes: challenges of determining pathogenicity.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
2
German Cancer Consortium (DKTK), partner site Freiburg, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
3
Department of Urology, Medical Faculty-University of Freiburg, Breisacher Str. 66, Freiburg, Germany.
4
North West Thames Regional Genetics Service, London North West University Healthcare NHS Trust, Harrow, UK.
5
Institute for Basic Research in Developmental Disabilities (IBR), Staten Island, NY, USA.
6
Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
7
Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
8
Department of Biomedical Informatics, Columbia University Medical Center, New York, NY, USA.
9
Great Ormond Street Hospital, Great Ormond Street, London, UK.
10
Stanley Institute for Cognitive Genomics, One Bungtown Road, Cold Spring Harbor Laboratory, NY, USA.
11
Kaiser Permanente Center for Health Research, Portland, OR, USA.
12
Genome Medical, South San Francisco, CA, USA.
13
Department of Biomedical and Preclinical Sciences, GIGA-R, Laboratory of Human Genetics, University of Liège, Liège, Belgium.
14
Institut National de Recherche Biomédicale, Kinshasa, DR, Congo.
15
Centre for Human Genetics, Faculty of Medicine, University of Kinshasa, DR, Congo.
16
Centre for Human Genetics, University Hospital, University of Leuven, Leuven, Belgium.
17
Genetics of Learning Disability Service, Newcastle, NSW, Australia.
18
School of Women's and Children's Health, University of New South Wales, Randwick, NSW, Australia.
19
Rare Disease Institute, Children's National Health System, Washington, District of Columbia, USA.
20
Department of Clinical Genetics, Liverpool Hospital, Sydney, Australia.
21
West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UK.
22
Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Medical Center, Nijmegen, The Netherlands.
23
Genetic Services of Western Australia, Undiagnosed Diseases Program, Perth, Western Australia, Australia.
24
Western Australian Register of Developmental Anomalies, Perth, Western Australia, Australia.
25
Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia.
26
Telethon Kids Institute, Perth, Western Australia, Australia.
27
University of Western Australia, School of Medicine, Division of Paediatrics, Perth, Western Australia, Australia.
28
Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
29
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
30
University of Melbourne, Melbourne, Victoria, Australia.
31
Australian Genomics Health Alliance, Melbourne, Victoria, Australia.
32
Center for Medical Genetics Dr. Jacinto de Magalhães, Hospital and University Center of Porto, Porto, Portugal.
33
unIGENe, and Center for Predictive and Preventive Genetics (CGPP), Institute for Molecular and Cell Biology (IBMC), Institute of Health Research and Innovation (i3S), University of Porto, Porto, Portugal.
34
Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MI, USA.
35
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
36
Department of Pediatrics, Division of Pediatric Neurology, University of Texas Southwestern, Dallas, TX, USA.
37
INSERM U1231, LNC UMR1231 GAD, Burgundy University, Dijon, France.
38
Reference Center for Developmental Anomalies, Department of Medical Genetics, Bordeaux University Hospital, Bordeaux, France.
39
Clinical Genetics, Guy's Hospital, Great Maze Pond, London, UK.
40
Indiana University School of Medicine, Department of Neurology, Indianapolis, IN.
41
GeneDx, 207 Perry Parkway, Gaithersburg, MD, USA.
42
New South Wales Health Pathology Genomic Laboratory, Prince of Wales Hospital, Randwick, Australia.
43
Spectrum Health Division of Medical and Molecular Genetics, Grand Rapids, MI, USA.
44
Department of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia.
45
Department of Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
46
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
47
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
48
Texas Children's Hospital, Houston, TX, USA.
49
Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, NSW, Australia.
50
Neuroscience Research Australia, University of New South Wales, Sydney, Australia.
51
Divisions of Newborn Medicine and Genetics & Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
52
Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, MD, USA.
53
Wellcome Trust Sanger Institute, Cambridgeshire, UK.
54
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
55
Biology PhD Program, The Graduate Center, The City University of New York, NY, USA.

Abstract

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X. This article is protected by copyright. All rights reserved.

KEYWORDS:

Cornelia de Lange; MRXS33 intellectual disability syndrome; TAF1; exome sequencing; transcriptomopathy

PMID:
31646703
DOI:
10.1002/humu.23936

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