MARK4 – Neurodevelopmental Disorder

MARK4 is a serine/threonine kinase involved in microtubule dynamics and mTOR pathway regulation. A recent report describes a heterozygous gain-of-function variant c.604T>C (p.Phe202Leu) in two siblings with childhood-onset neurodevelopmental disorder characterized by global developmental delay and intellectual disability (PMID:38041405). The variant resides in the catalytic domain and is absent from population databases. The siblings inherited the change from an unaffected, somatic mosaic mother, consistent with autosomal dominant inheritance but without additional segregation. No other families have been reported to date, and no other pathogenic variants in MARK4 have been linked to this phenotype. The clinical features include behavioral abnormalities and dysmorphic facial features alongside developmental impairment.

Functional assays demonstrate that p.Phe202Leu does not alter MARK4 expression but significantly increases phosphorylation of tau isoforms and ribosomal protein S6, indicating mTORC1 pathway upregulation (PMID:38041405). This gain-of-function effect provides mechanistic support for pathogenicity. No conflicting evidence or alternative gene associations have been described. Given the limited number of affected individuals, the gene–disease association is classified as Limited clinical validity. Genetic evidence is Limited based on a single sib-pair, while functional evidence is Moderate owing to robust in vitro kinase data. Further studies in independent cohorts are needed. Key take-home: MARK4 sequencing should be considered in patients with unexplained global developmental delay and intellectual disability to inform diagnosis and potential mTOR-targeted therapies.

References

• HGG advances • 2024 • Gain-of-function MARK4 variant associates with pediatric neurodevelopmental disorder and dysmorphism. PMID:38041405

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