A rare recurring gain-of-function variant in BMPR2 causes neurodevelopmental phenotypes in humans and flies.

A rare recurrent BMPR2 variant (c.1126G>A [p.Glu376Lys]) acts as a gain-of-function mutation causing neurodevelopmental phenotypes in humans and flies.

• Why it matters: Understanding genetic causes of neurodevelopmental disorders is crucial, especially when related to signaling pathways like BMP, which are involved in neural development. This variant's role in neurodevelopmental phenotypes highlights a potential target for diagnosis or intervention.
• What they did: Researchers identified the de novo BMPR2 variant in six individuals with autism spectrum disorder and developmental delay, and used Drosophila models to show that the variant behaves as a ligand-independent, hypermorphic allele that induces excessive BMP signaling and neurodevelopmental defects.
• The result: The findings suggest that ectopic activation of BMP signaling by this gain-of-function variant may contribute to neurodevelopmental disorders, and that BMPR2-specific inhibitors can suppress its hyperactivity, offering potential therapeutic insights.