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

BMPR2

Recurrent missense BMPR2 variant (p.Glu376Lys) acting as a hypermorphic gain-of-function allele that activates BMP signalling independently of ligand but dependently on type-1 BMP receptors

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.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The central message is the inversion of mechanism: the same gene, loss of function in pulmonary arterial hypertension, gain of function in a neurodevelopmental disorder, which forbids transposing to this variant the interpretation rules that hold for BMPR2 loss-of-function variants. Recurrence, de novo occurrence in at least five of six individuals and in vivo functional demonstration form a solid body of evidence for classifying p.Glu376Lys when it is found in a neurodevelopmental exome, but nothing allows extending it to other missense variants of the gene, and the described phenotype (autism, global delay) remains poorly specific. Suppression of the phenotype by BMPR2 inhibitors is shown only in Drosophila and does not, at this stage, constitute a validated therapeutic lead.

Analysis by Dr Thibaut Benquey