Clinical genomics, read and reviewed for you

BMPR2 encodes an evolutionarily conserved serine/threonine kinase that phosphorylates type-1 BMP receptors to mediate intercellular communication upon ligand binding; loss-of-function variants are known to cause pulmonary arterial hypertension and other cardiovascular disorders. The authors report a rare recurrent missense variant, c.1126G>A (NM_001204; p.Glu376Lys), identified in six individuals who all present with neurodevelopmental phenotypes including autism spectrum disorder and global developmental delay; trio analysis demonstrates de novo occurrence in at least five of them. In Drosophila, the variant behaves as a gain-of-function allele acting in a ligand-independent but type-1 BMP receptor-dependent manner, and BMPR2-specific inhibitors suppress the excessive BMP activation induced by its expression, demonstrating its hypermorphic property. Expressed in neurons or glial cells, it also causes neurodevelopmental defects in flies, and the authors propose that ectopic activation of BMP signalling across several brain cell types contributes to the phenotypes seen in the probands.