[Published in Nature] Meningomyelocele Linked to De Novo Genetic Mutations, According to Landmark Study

Meningomyelocele (MM), the most common structural defect of the human central nervous system, is a severe congenital condition that typically requires surgical intervention shortly after birth. While environmental factors such as folic acid deficiency have been known to influence the risk, the exact genetic causes have long remained unclear.

A recent large-scale genomic study published in Nature has, for the first time, demonstrated a strong association between MM and de novo genetic mutations—those not present in either parent but arising spontaneously in the affected individual.

The international research effort, involving institutions from 15 countries—including the University of California, San Diego, Yonsei University College of Medicine, and the University of Texas at Austin—conducted whole-exome sequencing (WES) on 851 MM trios (affected child and both parents) and 732 control trios. The results revealed that approximately 22% of MM patients carried newly emerged mutations likely to disrupt gene function.

Strikingly, damaging mutations were identified in 187 genes, many of which are involved in pathways essential for neural tube closure. These include genes responsible for maintaining the cytoskeleton (actin and microtubule networks), Netrin-1 signaling, and chromatin-modifying enzymes.

The researchers further validated these findings in Xenopus (frog) embryos, where introducing the same mutations often led to incomplete neural tube closure—mirroring the pathology of MM. While some genes exerted their effects independently, others demonstrated a synergistic effect when mutated in combination, suggesting that MM may result from complex interactions between multiple genes and environmental factors.

This study marks the first large-scale confirmation of the role of de novo mutations in neural tube defects such as MM. The findings are expected to have significant implications for prenatal diagnosis and the development of personalized treatment strategies.