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

TitleMissense variants in TAF1 and developmental phenotypes: challenges of determining pathogenicity.
Publication TypeJournal Article
Year of Publication2019
AuthorsCheng, H, Capponi, S, Wakeling, E, Marchi, E, Li, Q, Zhao, M, Weng, C, Stefan, PG, Ahlfors, H, Kleyner, R, Rope, A, Lumaka, A, Lukusa, P, Devriendt, K, Vermeesch, J, Posey, JE, Palmer, EE, Murray, L, Leon, E, Diaz, J, Worgan, L, Mallawaarachchi, A, Vogt, J, de Munnik, SA, Dreyer, L, Baynam, G, Ewans, L, Stark, Z, Lunke, S, Gonçalves, AR, Soares, G, Oliveira, J, Fassi, E, Willing, M, Waugh, JL, Faivre, L, Riviere, J-B, Moutton, S, Mohammed, S, Payne, K, Walsh, L, Begtrup, A, Sacoto, MJGuillen, Douglas, G, Alexander, N, Buckley, MF, Mark, PR, Adès, LC, Sandaradura, SA, Lupski, JR, Roscioli, T, Agrawal, PB, Kline, AD, Wang, K, Timmers, HTMarc, Lyon, GJ
Corporate AuthorsDeciphering Developmental Disorders study
JournalHum Mutat
Date Published2019 Oct 23

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.

Alternate JournalHum Mutat
PubMed ID31646703
PubMed Central IDPMC7187541
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
U01 HG008680 / HG / NHGRI NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom
R01 LM012895 / LM / NLM NIH HHS / United States