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

Abstract

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 450 |

Early Pregnancy Exposure to Ambient Air Pollution among Late-Onset Preeclamptic Cases Is Associated with Placental DNA Hypomethylation of Specific Genes and Slower Placental Maturation

“…It has a binding site in the progesterone receptor gene promoter [129]. Variants of the gene or disrupted expression are implicated in neurodevelopment [130,131] but mutated variants of TAF1 have also been implicated in cancer [132]. Additionally, here, we suggest that the impact these transcriptions factors have on molecular mechanisms in tumor growth and metastasis can be extrapolated to similar processes during placenta formation.…”

Dystonia-specific mutations in THAP1 alter transcription of genes associated with neurodevelopment and myelin

“…This list currently includes genes such as TOR1A (MIM: 605204), in which a single mutation has been linked to dystonia in multiple populations (DYT1 [MIM: 128100]), 71 6,40 In some of these genes harboring multiple mutations (e.g., THAP1, GNAL, and ANO3), genetic variation results in a largely consistent neurologic phenotype, whereas in others, such as ATP1A3 and TAF1, diverse mutations result in distinct clinical syndromes. [72][73][74][75] Dissecting the complex relationships between genetic variation and human disease requires a better understanding of their functional outcomes, the ways in which they differ, and in particular, the affected cellular pathways that they share.…”

Transcription Pause and Escape in Neurodevelopmental Disorders

“…The X-linked gene TAF1 encodes for the largest subunit of TFIID and its mutation is also most frequently described to cause neurodevelopmental delay ( Stenson et al, 2014 ; Niranjan et al, 2015 ; Hu et al, 2016 ; Gudmundsson et al, 2019 ; Kahrizi et al, 2019 ; Okamoto et al, 2020 ). Two large studies have described a total of 41 individuals that present with global developmental delay, ID, microcephaly, short stature, characteristic facial dysmorphologies and generalized hypotonia ( O’Rawe et al, 2015 ; Cheng et al, 2019 ). Two of these individuals were initially diagnosed with CdLS (see below) due to their craniofacial features, growth failure, ID and specific limb malformations.…”