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

Cheng, H., Capponi, S., Wakeling, E., Marchi, E., Li, Q., Zhao, M., Weng, C., Stefan, P. G., Ahlfors, H., Kleyner, R., Rope, A., Lumaka, A., Lukusa, P., Devriendt, K., Vermeesch, J., Posey, J. E., Palmer, E. E., Murray, L., Leon, E., Diaz, J., Worgan, L., Mallawaarachchi, A., Vogt, J., de Munnik, S. A., Dreyer, L., Baynam, G., Ewans, L., Stark, Z., Lunke, S., Goncalves, A. R., Soares, G., Oliveira, J., Fassi, E., Willing, M., Waugh, J. L., Faivre, L., Riviere, J. B., Moutton, S., Mohammed, S., Payne, K., Walsh, L., Begtrup, A., Guillen Sacoto, M. J., Douglas, G., Alexander, N., Buckley, M. F., Mark, P. R., Ades, L. C., Sandaradura, S. A., Lupski, J. R., Roscioli, T., Agrawal, P. B., Kline, A. D., Wang, K., Timmers, H. T. M., Lyon, G. J. (October 2019) Missense variants in TAF1 and developmental phenotypes: challenges of determining pathogenicity. Hum Mutat. ISSN 1059-7794

URL: https://www.ncbi.nlm.nih.gov/pubmed/31646703
DOI: 10.1002/humu.23936

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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA regulation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > copy number variants
CSHL Authors:
Communities: CSHL labs > Lyon lab
Depositing User: Matthew Dunn
Date: 23 October 2019
Date Deposited: 08 Nov 2019 17:12
Last Modified: 08 Nov 2019 17:12
Related URLs:
URI: http://repository.cshl.edu/id/eprint/38666

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