Philadelphia, October 13, 2026 – Researchers from Children’s Hospital of Philadelphia (CHOP) have discovered the mechanisms of previously unknown changes in a gene that result in symptoms associated with a neurodevelopmental disorder. The findings underscore the importance of a critical pathway and its role in brain development. The findings were published today in the American Journal of Human Genetics .
MAP2K4 is an enzyme that activates the c-Jun N-terminal kinase (JNK) pathway, an essential pathway for human neurodevelopment. While several prior studies have demonstrated that a loss in MAP2K4 is associated with multiple types of cancer, variants in the gene that produces the enzyme have not been linked to disease. However, other genes linked to the JNK pathway have been associated with genetic disorders, and the gene has been linked as a potential cause of neurodevelopmental disorders.
In this study, researchers identified nine patients with de novo MAP2K4 variants – meaning that the variant was not inherited from either parent – and one additional patient with an MAP2K4 variant of unknown inheritance. These patients exhibited several symptoms associated with a neurodevelopmental disorder, including developmental delay, epilepsy and congenital malformations.
“As a pediatric clinical geneticist and researcher, it’s always been important to me for every child to learn what their diagnosis is,” said first study author Tomoki Nomakuchi, MD, PhD , an attending physician with the Division of Genetic and Genomic Medicine at CHOP. “Only half of children with a suspected genetic syndrome get an answer even with our best technology, and every time we discover a new syndrome, that’s a few more families to have the door opened to better prognosis, research opportunities, and eventually, targeted treatments.”
Beyond simply identifying the patients, the researchers wanted to understand the mechanisms taking place at a molecular level that result in these symptoms. The study team developed CRISPR-edited induced pluripotent stem cell-derived neurons with MAP2K4 deficiency, providing a platform for pathological modeling and preclinical testing to understand this novel disorder. These stem cells revealed a variety of negative effects on the JNK pathway, providing a better understanding of the pathway’s role in healthy neurodevelopment and a potential therapeutic target for further study.
“Neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases have implicated the JNK pathway, which, when adding the findings of this study, underscore the remarkable importance of this pathway across the lifespan,” said co-senior author Elizabeth Bhoj, MD, PhD , an attending physician in the Division of Genetic and Genomic Medicine at CHOP. “While more preclinical work is needed to truly understand and appreciate the role MAP2K4 may have in neurodevelopmental disorders, these findings represent the first critical steps necessary toward identifying and potentially treating this previously unknown patient community.”
This study was supported by National Institutes of Health grants K08 NS140553 and T32 GM008638 and in part by a grant from the Chan-Zuckerberg Initiative. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Nomakuchi et al, “ De novo MAP2K4 variants cause a neurodevelopmental syndrome and impaired JNK signaling in iPSC-derived neurons.” Am J Hum Genet . Online October 13, 2026. DOI: 10.1016/j.ajhg.2026.09.014.
About Children’s Hospital of Philadelphia:
A non-profit, charitable organization, Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network , which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania, New Jersey, and Delaware. CHOP also operates the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia, the Behavioral Health and Crisis Center (including a 24/7 Crisis Response Center) and the Center for Advanced Behavioral Healthcare , a mental health outpatient facility. Its unique family-centered care and public service programs have brought Children’s Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit https://www.chop.edu.
American Journal of Human Genetics
Experimental study
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De novo MAP2K4 variants cause a neurodevelopmental syndrome and impaired JNK signaling in iPSC-derived neurons
13-Oct-2026