Objective: We set out to discover the genetic basis of an X-linked genetic syndrome presenting with global developmental delay, intellectual disability, characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male cases.

Background: TAF1 is the largest subunit of the TFIID complex, and has been ranked 53rd among the top 1,003 constrained human genes, suggesting a critical role for this protein in normal cellular function. The genomic region containing TAF1 has also been suggested to play an important role in a condition in the Philippines called X-linked dystonia-parkinsonism (XDP). XDP is an X-linked recessive movement disorder characterized by adult onset dystonia and parkinsonism, which leads to eventual death due to oropharyngeal dystonia or secondary infections. Studies investigating the molecular basis of XDP demonstrated aberrant neuron-specific TAF1 isoform expression levels in neuronal tissue containing TAF1 variants. A reduction in TAF1 expression is associated with large-scale expression differences across hundreds of genes, and studies in rat and mice brain also corroborate the relevance of TAF1 expression patterns specific to neuronal tissues.

Methods: Several strategies were used to identify candidate disease-related sequence variation. These included whole genome sequencing, exome sequencing, targeted gene panel sequencing and microarray-based strategies. Sanger sequencing was used to validate sequence variations.

Results: We have found thus far twelve families with overlapping clinical presentations and with de novo or maternally inherited mutations in TAF1. Two additional families harboring large duplications involving TAF1 have phenotypic overlap with the probands harboring missense mutations, but they also demonstrate a severe neurodegeneration phenotype. RNA-seq for one of the families suggests that the phenotype is associated with down regulation of a set of genes notably enriched for genes regulated by E-box proteins, and knockdown and mutant studies for this gene in zebrafish have a quantifiable, albeit small, effect on a neuronal phenotype.

Conclusions: Our results implicate mutations in TAF1 as playing a critical role in the development of this X-linked intellectual disability syndrome, with implications related to the pathogenesis of X-linked dystonia-parkinsonism.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-rare-genetic-transcriptomopathy-syndrome-involving-taf1-leading-to-insights-into-more-common-neurologic-disorders-including-x-linked-dystonia-parkinsonism-xdp/