Inactivating mutations in polyadenylation factor CSTF2 disrupt intronic polyadenylation patterns and are associated with intellectual disability.

In ten hemizygous male probands with intellectual disability, rare CSTF2 variants disrupt intronic polyadenylation-site usage, with strongly impairing variants reducing intronic sites and shifting 3′UTR polyadenylation downstream.

• Why it matters: Alternative polyadenylation is prominent during neuronal differentiation, but how monogenic neurodevelopmental disorders perturb intronic polyadenylation patterns is not well defined.
• What they did: The study identified seven rare CSTF2 variants across missense, nonsense, splice-site, and frameshift changes, then tested selected variants in CSTF2-depleted cells using RNA sequencing and 3′-end-proximal sequencing.
• The result: Phe19Leu, Gln543ter, and Leu555Ser predominantly reduced intronic polyadenylation while increasing downstream terminal 3′UTR usage; Asp50Ala showed the opposite pattern, supporting CSTF2 dysregulation as an X-linked neurodevelopmental disorder mechanism.

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