De novo putative loss-of-function variants in TAF4 are associated with a neuro-developmental disorder

Beau D E Janssen; Marie-Jose H van den Boogaard; Klaske Lichtenbelt; Eleanor G Seaby; Karen Stals; Sian Ellard; Ruth Newbury-Ecob; Abhijit Dixit; Laura Roht; Sander Pajusalu; Katrin Õunap; Helen V Firth; Michael Buckley; Meredith Wilson; Tony Roscioli; Timothy Tidwell; Rong Mao; Sarah Ennis; Sjoerd J Holwerda; Koen van Gassen; Richard H van Jaarsveld

doi:10.1002/humu.24444

De novo putative loss-of-function variants in TAF4 are associated with a neuro-developmental disorder

Hum Mutat. 2022 Dec;43(12):1844-1851. doi: 10.1002/humu.24444. Epub 2022 Aug 10.

Authors

Beau D E Janssen¹, Marie-Jose H van den Boogaard¹, Klaske Lichtenbelt¹, Eleanor G Seaby², Karen Stals³, Sian Ellard^{3

4}, Ruth Newbury-Ecob⁵, Abhijit Dixit⁶, Laura Roht^{7

8}, Sander Pajusalu^{7

8}, Katrin Õunap^{7

8}, Helen V Firth⁹, Michael Buckley¹⁰, Meredith Wilson¹¹, Tony Roscioli^{10

12

10}, Timothy Tidwell¹³, Rong Mao^{13

14}, Sarah Ennis², Sjoerd J Holwerda¹, Koen van Gassen¹, Richard H van Jaarsveld¹

Affiliations

¹ Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
² Genomic Informatics Group, University of Southampton, Southampton, UK.
³ Exeter Genomic Laboratory, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK.
⁴ Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
⁵ Clinical Genetics, St Michael's Hospital Bristol, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
⁶ Department of Clinical Genetics, Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁷ Department of Clinical Genetics, Tartu University Hospital, Tartu, Estonia.
⁸ Department of Clinical Genetics, Institute of Clinical Medicine, Tartu University, Tartu, Estonia.
⁹ Wellcome Sanger Institute, Cambridge, UK.
¹⁰ Randwick Genomics laboratory, New South Wales Health Pathology, Sydney, New South Wales, Australia.
¹¹ Department of Clinical Genetics, Children's Hospital at Westmead, and Discipline of Genomic Medicine, University of Sydney, Sydney, New South Wales, Australia.
¹² Neurosciences Research Australia, University of NSW, Kensington, New South Wales, Australia.
¹³ ARUP Laboratories, Salt Lake City, Utah, USA.
¹⁴ Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA.

Abstract

TATA-binding protein associated factor 4 (TAF4) is a subunit of the Transcription Factor IID (TFIID) complex, a central player in transcription initiation. Other members of this multimeric complex have been implicated previously as monogenic disease genes in human developmental disorders. TAF4 has not been described to date as a monogenic disease gene. We here present a cohort of eight individuals, each carrying de novo putative loss-of-function (pLoF) variants in TAF4 and expressing phenotypes consistent with a neuro-developmental disorder (NDD). Common features include intellectual disability, abnormal behavior, and facial dysmorphisms. We propose TAF4 as a novel dominant disease gene for NDD, and coin this novel disorder "TAF4-related NDD" (T4NDD). We place T4NDD in the context of other disorders related to TFIID subunits, revealing shared features of T4NDD with other TAF-opathies.

Keywords: TAF4; TFIID; human genetics; mendelian disorders; neurodevelopmental disorder.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Child
Developmental Disabilities / genetics
Humans
Neurodevelopmental Disorders* / diagnosis
Neurodevelopmental Disorders* / genetics
Phenotype
TATA-Binding Protein Associated Factors* / genetics
TATA-Binding Protein Associated Factors* / metabolism
Transcription Factor TFIID* / genetics
Transcription Factor TFIID* / metabolism

Substances

TATA-Binding Protein Associated Factors
Transcription Factor TFIID
TAF4 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding