Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity

Hanyin Cheng, Simona Capponi, Emma Wakeling, Elaine Marchi, Quan Li, Mengge Zhao, Chunhua Weng, Piatek G. Stefan, Helena Ahlfors, Robert Kleyner, Alan Rope, Aimé Lumaka, Prosper Lukusa, Koenraad Devriendt, Joris Vermeesch, Jennifer E. Posey, Elizabeth E. Palmer, Lucinda Murray, Eyby Leon, Jullianne DiazLisa Worgan, Amali Mallawaarachchi, Julie Vogt, Sonja A. de Munnik, Lauren Dreyer, Gareth Baynam, Lisa Ewans, Zornitza Stark, Sebastian Lunke, Ana R. Gonçalves, Gabriela Soares, Jorge Oliveira, Emily Fassi, Marcia Willing, Jeff L. Waugh, Laurence Faivre, Jean Baptiste Riviere, Sebastien Moutton, Shehla Mohammed, Katelyn Payne, Laurence Walsh, Amber Begtrup, Maria J. Guillen Sacoto, Ganka Douglas, Nora Alexander, Michael F. Buckley, Paul R. Mark, Lesley C. Adès, Sarah A. Sandaradura, James R. Lupski, Tony Roscioli, Pankaj B. Agrawal, Antonie D. Kline, Kai Wang, H. T.Marc Timmers, Gholson J. Lyon

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability [ID] syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TATA-box binding protein associated factor 1 (TAF1), which participates in RNA polymerase II transcription. The initial study reported 11 families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into ID and/or autism spectrum disorder. 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 modeling 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 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 the TAF1/MRXS33 ID 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 a gene mapping to chromosome X.

Original languageEnglish (US)
Pages (from-to)449-464
Number of pages16
JournalHuman mutation
Issue number2
StatePublished - Feb 1 2020


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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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