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A Copernican revolution of multigenic analysis: A retrospective study on clinical exome sequencing in unclear genetic
M Chetta1, M Tarsitano1, M Rivieccio1
1A.O.R.N. A. Cardarelli Hospital's Laboratory of Medical Genetics and Genomics, Naples, Italy.
Insights
This study highlights how analyzing the full clinical exome, not just single genes, improves rare genetic disease diagnosis. This approach maximizes Next-Generation Sequencing data utility for better patient management.
Area of Science:
- Genetics
- Medical Genomics
- Rare Diseases
Background:
- Mendelian diseases, caused by single gene variants, have historically shaped medical understanding.
- The monogenic approach underutilizes comprehensive Next-Generation Sequencing (NGS) data.
- A shift towards multigenic analysis is crucial for understanding complex disease etiology.
Purpose of the Study:
- To evaluate the diagnostic utility of clinical exome analysis in patients with specific rare genetic disorders.
- To demonstrate a novel pipeline for analyzing genetic variants, including variants of uncertain significance (VUS).
- To emphasize the importance of a comprehensive genetic analysis approach for rare disease diagnosis.
Main Methods:
- Retrospective analysis of clinical exome data from 32 probands.
- Gene enrichment analysis using SOPHiA-DDM-v4 software on *.VCF files.
- Filtering for pathogenic/likely pathogenic variants and VUS with autosomal dominant inheritance, compound heterozygotes, and MAF < 0.05%.
Main Results:
- The study assessed patients with autoinflammation, hemolytic uremic syndrome, and Waldenström macroglobulinemia.
- A gene enrichment strategy was employed to identify relevant genetic variants.
- The pipeline focused on analyzing a broader set of patient gene assets.
Conclusions:
- Analyzing the complete clinical exome enhances the diagnostic yield for rare genetic disorders.
- This approach offers new insights into the genetic basis of complex diseases.
- Integrating this comprehensive analysis into clinical practice can improve patient care for rare genetic conditions.
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.
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