De novo MAP2K4 variants cause a novel neurodevelopmental syndrome with impaired JNK signaling in iPSC-derived neurons

Abstract

MAP2K4 encodes a kinase that activates the c-Jun N-terminal kinase (JNK) pathway, which is essential for human neurodevelopment. While somatic MAP2K4 loss has been observed in cancer, germline variants have not previously been linked to human disease. We describe ten individuals with de novo or presumed de novo MAP2K4 variants who present with a novel syndromic neurodevelopmental disorder. Shared features include developmental delay or intellectual disability, epilepsy, and variable congenital malformations, most commonly affecting the genitourinary system. To define the mechanism, we generated CRISPR-edited iPSC-derived neurons with MAP2K4 deficiency. These neurons showed reduced JNK pathway activation and abnormal differentiation, characterized by persistence of progenitor-like cells and disrupted neurite morphology. Our findings establish MAP2K4 as a Mendelian neurodevelopmental disorder gene and identify impaired JNK signaling as the underlying mechanism. More broadly, this work expands the spectrum of JNK-pathway disorders and underscores the critical role of JNK signaling in human brain development.