Clinical Exome Sequencing as a Key Diagnostic Tool: A Rare de novo TRIO Variant in Dizygotic Twins

Introduction: TRIO-associated neurodevelopmental disorders are rare genetic conditions caused by pathogenic variants in the TRIO gene, which plays a crucial role in neuronal development. Mutations in the TRIO gene are increasingly associated with autosomal dominant inheritance. However, de novo occurrences in dizygotic twins remain rare and poorly understood. Case Presentation: In this work, clinical exome sequencing (CES) was performed on dizygotic twin sisters who presented with neurodevelopmental delay, intellectual disability, behavioral issues, and microcephaly. Segregation analysis using conventional Sanger sequencing was conducted on the parents to assess the inheritance pattern. A pathogenic missense variant c.4283G>A (p.Arg1428Gln) in the GEFD1 domain of the TRIO gene was identified. This variant is known to reduce GEF activity toward Rac1, impacting neuronal signaling pathways. Segregation analysis did not detect the variant in the parents, and mosaicism remains a possibility that could not be fully ruled out due to the limitations of this technique. Despite the lack of a definitive molecular diagnosis in the parents, detailed genetic counseling was provided to the family. Conclusion: These findings highlight the diagnostic value of CES in rare neurodevelopmental disorders and suggest a plausible but unproven parental germline or early postzygotic mosaic event, while acknowledging alternative explanations.