Distinct heterozygous TTC7A missense variants lead to different intestinal epithelial phenotypes in pediatric IBD

Pathogenic mutations in Tetratricopeptide repeat domain 7A ( TTC7A ) result in gastrointestinal and immunological disorders of which the pathobiology is not fully understood. Previous case reports indicate that TTC7A plays an important role in preserving intestinal epithelial integrity, but thus far only few variants have been investigated and it is unclear if different variants exert the same effects. Here, we aim to study the effects of different variants on the intestinal epithelium. We present three instances of pediatric inflammatory bowel disease (IBD), displaying varying clinical symptoms and severity levels, and associated with different heterozygous missense mutations in TTC7A . Intestinal organoids derived from patients show dissimilar epithelial phenotypes and exhibit differences in growth, morphology, apicobasal polarity, responses to specific drugs, TTC7A expression, and transcriptional profiles. The findings of our study suggest differences in pathobiology between individuals with different TTC7A mutations. This investigation enhances our comprehension of TTC7A-related conditions and can have implications for developing targeted therapies for TTC7A-associated disorders.