Dual molecular mechanisms and functional compensation by RBMXL1 retrocopy underlie RBMX-associated neurodevelopmental syndrome

Here, we provide definitive evidence from nine unrelated families that RBMX variants lead to neurodevelopmental disorders characterised by intellectual disability, brain malformations, microcephaly, and microphthalmia. Combining in vitro and in vivo experiments in human and mouse models, we show that RBMX pathogenic variants disrupt cortical development through both loss- and gain-of-function mechanisms.

Despite severe phenotypes in humans, Rbmx-deficient mice display only mild cortical abnormalities, which we attribute to partial compensation by Rbmxl1, a retrocopy that arose independently in mice and humans. We demonstrate that RBMX and RBMXL1 share protein and RNA partners and act redundantly during brain development, with RBMXL1 buffering the effect of RBMX loss. Our findings reveal that RBMX-related neurodevelopmental syndromes result from the interplay of opposing molecular mechanisms and retrocopy compensation, highlighting a previously unrecognized role for retrocopies in modulating disease severity.