STXBP1-related disorders – one or two disease mechanisms?

Haploinsufficiency. STXBP1-related disorders are one of the most common neurodevelopmental disorders due to pathogenic variants in a single gene. Haploinsufficiency is the proposed disease mechanism and a significant number of individuals have deletions or protein-truncating variants. However, there are also recurrent missense variants in STXBP1, which is often seen in diseases that have a different disease mechanism. In a recent publication in Nature Communications, some of the recurrent variants in STXBP1 are suggested to have an additional disease mechanism, a dominant-negative effect. In this blog post, I want to discuss how we can reconcile both observations and whether STXBP1-related disorders are a single entity with a common disease mechanism. Continue reading