Whole-exome sequencing revealed co-segregating variants in a multigenerational family with schizophrenia

Schizophrenia is a complex neuropsychiatric disorder with both genetic and environmental contributions. Despite extensive genome-wide studies identifying common risk variants, a substantial proportion of heritability remains unexplained. Whole-exome sequencing (WES) in multiplex families offers a valuable approach to identify rare, potentially high-impact variants segregating with disease. This study aimed to identify potentially relevant coding variants associated with schizophrenia in a multigenerational family. A four-generation multiplex family with schizophrenia was recruited, with one affected individual in each of three successive generations. WES was performed in seven individuals from the family (three affected and four unaffected). Variants were prioritised based on minor allele frequency (MAF < 0.01), predicted functional impact, and co-segregation patterns. Five candidate variants in genes previously implicated in neuropsychiatric pathways— rs2066471 (MTHFR), rs147953761 (CHI3L1), rs1490428731 and rs7645908 (DRD3), and rs165599 (COMT) MTHFR—were identified. These variants co-segregated with affected individuals inherited from grandmother to granddaughter through the father. These genes are involved in dopaminergic signalling, neuroinflammation, and folate metabolism, all of which have been associated with the pathophysiology of schizophrenia. This family-based WES study highlights potentially relevant variants in biologically plausible candidate genes and supports the contribution of the rare and common variants to the risk of schizophrenia. Further studies in larger cohorts and functional validation are required to establish their pathogenic role.