Gain-of-function MARK4 variant associates with pediatric neurodevelopmental disorder and dysmorphism.

Microtubule affinity-regulating kinase 4 (MARK4) is a serine/threonine kinase that plays a key role in tau phosphorylation and regulation of the mammalian target of rapamycin (mTOR) pathway. Abnormal tau phosphorylation and dysregulation of the mTOR pathway are implicated in neurodegenerative and neurodevelopmental disorders. Here, we report a gain-of-function variant in in two siblings with childhood-onset neurodevelopmental disability and dysmorphic features. The siblings carry a germline heterozygous missense variant c.604T>C (p.Phe202Leu), located in the catalytic domain of the kinase, which they inherited from their unaffected, somatic mosaic mother. Functional studies show that this amino acid substitution has no impact on protein expression but instead increases the ability of MARK4 to phosphorylate tau isoforms found in the fetal and adult brain. The variant also increases phosphorylation of ribosomal protein S6, indicating upregulation of the mTORC1 pathway. In this study, we link a germline monoallelic variant to a childhood-onset neurodevelopmental disorder characterized by global developmental delay, intellectual disability, behavioral abnormalities, and dysmorphic features.