WHOLE-GENOME SEQUENCING AS A FIRST-TIER TEST FOR SCHIZOPHRENIA AND BIPOLAR DISORDER: THE FRENCH CLINICAL IMPLEMENTATION

The integration of genomic medicine into healthcare systems represents a major translational challenge. In France, the Plan France Médecine Génomique 2025 (PFMG2025) was designed to directly embed whole-genome sequencing (WGS) into routine clinical care through a nationwide infrastructure combining sequencing platforms, standardized pipelines, and clinical networks. Unlike many initiatives initially rooted in research, PFMG2025 was conceived as a clinical-first program, enabling the large-scale implementation of genomics within a public healthcare system. Psychiatric indications were integrated into PFMG2025 in May 2020, initially restricted to so-called “syndromic schizophrenia” and prioritizing trio-based sequencing. At that stage, access to WGS required prior chromosomal microarray (CGH array) testing. However, the diagnostic yield of CGH arrays in this population proved to be very limited. In contrast, in the first 68 patients analyzed, WGS identified pathogenic or likely pathogenic variants (ACMG class IV–V) in 22.1% of cases, with an additional 25% of variants of uncertain significance (VUS). These results supported the clinical relevance of WGS in psychiatry and justified a paradigm shift toward its use as a first-tier test, along with an expansion of inclusion criteria. Since 2024, the French national framework has expanded to include patients with schizophrenia or bipolar disorder presenting at least one of the following features: early onset; neurodevelopmental features (e.g., intellectual disability, autism spectrum disorder); signs suggestive of a neurodegenerative disorder (e.g., cognitive decline, motor symptoms); treatment resistance or severe intolerance to psychotropic medications; a family history suggestive of a genetic condition or a sporadic presentation; associated dysmorphic features or somatic disease; or an atypical clinical course (e.g., visual hallucinations, catatonia). Importantly, trio sequencing is no longer mandatory, enabling broader access and improved feasibility in routine care. This expanded framework has demonstrated robust performance in real-world settings. Among 254 validated WGS requests, pathogenic or likely pathogenic variants (class IV–V) were identified in 18.7% of patients, with an additional 30% of VUS. These results confirm a sustained diagnostic yield comparable to other clinical indications and support the scalability of genome-first approaches in psychiatry. Here, we present the French clinical framework for deploying WGS in schizophrenia and bipolar disorder, including its historical evolution, diagnostic performance, and integration into national care pathways. We also discuss key challenges, including variant interpretation, ethical considerations, and future developments. Building on the infrastructure and experience of PFMG2025, this strategy enables the identification of rare variants with large effect sizes, offering opportunities for refined diagnosis, improved patient stratification, and the development of precision psychiatry approaches. Overall, this initiative illustrates a paradigm shift from stepwise genetic testing to genome-first strategies in psychiatry, positioning France at the forefront of clinical implementation in psychiatric genomics.