A Copernican revolution of multigenic analysis: A retrospective study on clinical exome sequencing in unclear genetic disorders.

ABSTRACT

Despite the inevitable shift in medical practice towards a deeper understanding of disease etiology and progression through multigenic analysis, the profound historical impact of Mendelian diseases cannot be overlooked. These diseases, such as cystic fibrosis and thalassemia, are characterized by a single variant in a single gene leading to clinical conditions, and have significantly shaped our medical knowledge and treatments. In this respect, the monogenic approach inevitably results in the underutilization of Next-Generation Sequencing (NGS) data. Herein, a retrospective study was performed to assess the diagnostic value of the clinical exome in 32 probands with specific phenotypic characteristics (patients with autoinflammation and immunological dysregulation, N = 20; patients diagnosed with Hemolytic uremic syndrome N = 9; and patients with Waldenström macroglobulinemia, N = 3). A gene enrichment analysis was performed using the *. VCF file generated by SOPHiA-DDM-v4. This analysis selected a subset of genes containing pathogenic or likely pathogenic variants with autosomal dominant (AD) inheritance. In addition, all variants of uncertain significance (VUS) were included, filtered by AD inheritance mode, the presence of compound heterozygotes, and a minor allele frequency (MAF) cutoff of 0.05 %. The aim of the pipeline described here is based on a perspective shift that focuses on analyzing patients' gene assets, offering new light on the complex interplay between genetics and disease presentation. Integrating this approach into clinical practices could significantly enhance the management of patients with rare genetic disorders.