A recurrent missense variant in the E3 ubiquitin ligase substrate recognition subunit FEM1B causes a rare syndromic neurodevelopmental disorder.

FEM1B acts as a substrate recognition subunit for ubiquitin ligase complexes belonging to the CRL2 E3 family. Several biological functions have been proposed for FEM1B, including a structurally resolved function as a sensor for redox cell status by controlling mitochondrial activity, but its implication in human disease remains elusive. To understand the involvement of FEM1B in human disease, we made use of Matchmaker exchange platforms to identify individuals with de novo variants in FEM1B and performed their clinical evaluation. We performed functional validation using primary neuronal cultures and in-utero electroporation assays, as well as experiments on patient's cells. Five individuals with a recurrent de novo missense variant in FEM1B were identified: NM_015322.5:c.377G>A NP_056137.1:p.(Arg126Gln) (FEM1B Overall, our data indicate that p.(Arg126Gln) induces aberrant FEM1B activation resulting in a gain-of-function mechanism associated with a severe syndromic developmental disorder in humans.

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