Abstract
Background/Objectives: Congenital scoliosis (CS) is a developmental disorder characterized by abnormal vertebral development during embryogenesis. Despite the identification of genes involved in vertebral development, the underlying genetic causes of CS remain largely unknown. Monozygotic (MZ) twins discordant for CS offer a unique opportunity to explore de novo or postzygotic causes. This exploratory case study aimed to investigate potential causative variants underlying CS using whole-exome sequencing (WES). Methods: We performed WES on a Kazakhstani family with MZ twins discordant for congenital scoliosis. Variant prioritization included homozygous mutation analysis in the affected twin, family-based comparisons via de novo, autosomal recessive, and autosomal dominant models, and cross-referencing with variants previously implicated in spinal deformities. Results: Key findings include potential associations of the STOX1 (storkhead box 1), HOXD8 (homeobox D8), and C1QTNF9 (C1q- and TNF-related 9) genes with congenital scoliosis. However, subsequent validation revealed low read depth and strand bias. Notably, no unique variants were detected in genes previously known to cause CS. Conclusions: The first WES analysis of CS-discordant twins from a single family highlights the feasibility of a combined family-based and twin-comparative analytical pipeline. Our results provide new insights into the genetic architecture of CS and establish a foundation for future twin studies to elucidate the genetic basis of rare developmental disorders.