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

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• A novel neurodevelopmental syndrome, TAF1/MRXS33 intellectual disability syndrome, was previously linked to pathogenic variants in the X-linked TAF1 gene.
• The syndrome initially presented with hypotonia, facial dysmorphia, and developmental delay evolving into intellectual disability (ID) and/or autism spectrum disorder (ASD).

Purpose of the Study:

• To identify additional families with TAF1/MRXS33 intellectual disability syndrome using a genotype-first approach.
• To broaden the understanding of the phenotypic spectrum and molecular defects associated with TAF1 variants.
• To explore the challenges in determining the pathogenicity of inherited missense variants in X-linked genes.

Main Methods:

• Genotype-first approach to identify 27 new families.
• Familial segregation analysis and clinical phenotyping.
• Bioinformatics and molecular modeling for variant pathogenicity assessment.
• Phenotypic clustering using 51 Human Phenotype Ontology (HPO) terms.

Main Results:

• Identification of 27 additional families with TAF1 variants.
• Expansion of the phenotypic spectrum, including brain morphological abnormalities, seizures, hearing loss, and heart malformations.
• Demonstration of considerable pleiotropy and clinical variability in TAF1-related disorders.
• Highlighting challenges in assessing pathogenicity of missense variants in X-linked genes.

Conclusions:

• The study significantly expands the known clinical presentation of TAF1/MRXS33 intellectual disability syndrome.
• It underscores the genetic and phenotypic heterogeneity associated with TAF1 variants.
• The findings emphasize the complexities of variant interpretation for X-linked genes.