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Free keywords:
Adolescent
Animals
Child
Child, Preschool
Developmental Disabilities/*genetics/metabolism/pathology
Disease Models, Animal
E-Box Elements
Facies
Family
Gene Expression Regulation
Histone Acetyltransferases/*genetics/metabolism
Humans
Infant
Inheritance Patterns
Intellectual Disability/*genetics/metabolism/pathology
Male
Mutation
Neurodegenerative Diseases/*genetics/metabolism/pathology
Pedigree
Phenotype
Signal Transduction
TATA-Binding Protein Associated Factors/*genetics/metabolism
Transcription Factor TFIID/*genetics/metabolism
Young Adult
Zebrafish
Abstract:
We describe an X-linked genetic syndrome associated with mutations in TAF1 and manifesting with global developmental delay, intellectual disability (ID), characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male individuals. Simultaneous studies using diverse strategies led to the identification of nine families with overlapping clinical presentations and affected by de novo or maternally inherited single-nucleotide changes. Two additional families harboring large duplications involving TAF1 were also found to share phenotypic overlap with the probands harboring single-nucleotide changes, but they also demonstrated a severe neurodegeneration phenotype. Functional analysis with RNA-seq for one of the families suggested that the phenotype is associated with downregulation of a set of genes notably enriched with genes regulated by E-box proteins. In addition, knockdown and mutant studies of this gene in zebrafish have shown a quantifiable, albeit small, effect on a neuronal phenotype. Our results suggest that mutations in TAF1 play a critical role in the development of this X-linked ID syndrome.
