Co-Occurrence of RAD21 and TNFAIP3 Mutations in Cornelia de Lange Syndrome with Pustular Psoriasis: Potential...

Cornelia de Lange Syndrome (CdLS) is a rare multisystem developmental disorder caused primarily by mutations in cohesin complex genes, including RAD21. Psoriasis is a chronic inflammatory skin disease linked to immune dysregulation, notably involving TNFAIP3 (A20), a negative regulator of NF-κB signaling. Although case reports have suggested a possible coexistence of CdLS and psoriasis, the underlying molecular basis has remained unexplored. Here we report the first case of molecular co-occurrence of CdLS and generalized pustular psoriasis in a patient with novel heterozygous nonsense variant in RAD21 (c.1306C>T, p.Gln436*), pathogenic for CdLS type 4, and a previously unreported truncating variant in TNFAIP3 (c.2199C>A, p.Cys733*), predicted to disrupt NF-κB regulation and classified as a variant of uncertain significance. Structural protein modeling showed significant conformational disruption in RAD21 and partial truncation of the ZnF domains of TNFAIP3, supporting their functional impact. This study is the first to suggest a possible molecular mechanism that may explain the rare co-occurrence of CdLS and psoriasis: RAD21 deficiency disrupts chromatin architecture and immune gene regulation, while TNFAIP3 loss-of-function removes critical NF-κB inhibition, resulting in synergistic developmental and inflammatory phenotypes. Secondary transcriptomic data analysis further suggests that RAD21 knockdown may downregulate TNFAIP3 expression, providing a possible mechanistic intersection. Our findings provide the first molecular evidence linking RAD21 and TNFAIP3, introducing a novel pathogenic hypothesis connecting cohesin dysfunction and immune dysregulation. This work expands the mutational spectrum of both genes and opens a new avenue for understanding developmental-inflammatory disease overlap.