Whole exome sequencing uncovers novel genetic insights into Tethered cord syndrome

Tethered cord syndrome (TCS) is a neurodevelopmental disorder associated with neural tube defects (NTD), yet its genetic underpinnings remain poorly characterized. To elucidate its molecular basis, we conducted whole-exome sequencing (WES) on 81 TCS patients. Our analysis revealed that MNX1 variants, including two microdeletions and a deleterious missense variant, accounted for 3.7% (3/81) of cases in this cohort. Furthermore, gene-based collapsing analysis against 5,000 healthy controls revealed eight genes significantly enriched for loss of function variants and nine genes with an excess burden of damaging missense variants in TCS patients. Additionally, TCS patients exhibited a significantly higher burden of damaging missense variants in NTD-related genes. We also identified a trigenic variant combination (AFDN/PCSK5/PRICKLE4) exclusively in TCS patients, suggesting potential oligogenic inheritance in TCS. Collectively, our findings expand the genetic architecture of TCS, highlight novel pathogenic mechanisms, and provide insights for future clinical surveillance.