Developing a scoring system for gene curation prioritization in lysosomal diseases.
Autor: | Vernet Machado Bressan Wilke M; Department of Pathology and Immunology, Washington University in St. Louis, MO, United States of America., Goldstein J; University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America., Groopman E; Children's National Hospital, Washington, DC, United States of America., Mohan S; University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America., Waddell A; University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America., Fernandez R; American College of Genetics and Genomics, Bethesda, MD, United States of America., Chen H; Prevention Genetics, part of Exact Sciences, Marshfield, WI, United States of America., Bali D; Duke University Health System, Durham, NC, United States of America., Baudet H; University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America., Clarke L; University of British Columbia, Vancouver, Canada., Hung C; Invitae, San Francisco, CA, United States of America., Mao R; ARUP Laboratories, Salt Lake City, UT, United States of America; University of Utah, Salt Lake City, UT, United States of America., Yuzyuk T; ARUP Laboratories, Salt Lake City, UT, United States of America; University of Utah, Salt Lake City, UT, United States of America., Craigen WJ; Baylor College of Medicine, Houston, TX, United States of America., Pinto E Vairo F; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States of America; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, United States of America. Electronic address: vairo.filippo@mayo.edu. |
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Jazyk: | angličtina |
Zdroj: | Molecular genetics and metabolism [Mol Genet Metab] 2024 Sep-Oct; Vol. 143 (1-2), pp. 108572. Date of Electronic Publication: 2024 Sep 05. |
DOI: | 10.1016/j.ymgme.2024.108572 |
Abstrakt: | Introduction: Diseases caused by lysosomal dysfunction often exhibit multisystemic involvement, resulting in substantial morbidity and mortality. Ensuring accurate diagnoses for individuals with lysosomal diseases (LD) is of great importance, especially with the increasing prominence of genetic testing as a primary diagnostic method. As the list of genes associated with LD continues to expand due to the use of more comprehensive tests such as exome and genome sequencing, it is imperative to understand the clinical validity of the genes, as well as identify appropriate genes for inclusion in multi-gene testing and sequencing panels. The Clinical Genome Resource (ClinGen) works to determine the clinical importance of genes and variants to support precision medicine. As part of this work, ClinGen has developed a semi-quantitative framework to assess the strength of evidence for the role of a gene in a disease. Given the diversity in gene composition across LD panels offered by various laboratories and the evolving comprehension of genetic variants affecting secondary lysosomal functions, we developed a scoring system to define LD (Lysosomal Disease Scoring System - LDSS). This system sought to aid in the prioritization of genes for clinical validity curation and assess their suitability for LD-targeted sequencing panels. Methods: Through literature review encompassing terms associated with both classically designated LD and LFRD, we identified 14 criteria grouped into "Overall Definition," "Phenotype," and "Pathophysiology." These criteria included concepts such as the "accumulation of undigested or partially digested macromolecules within the lysosome" and being "associated with a wide spectrum of clinical manifestations impacting multiple organs and systems." The criteria, along with their respective weighted values, underwent refinement through expert panel evaluation differentiating them between "major" and "minor" criteria. Subsequently, the LDSS underwent validation on 12 widely acknowledged LD and was later tested by applying these criteria to the Lysosomal Disease Network's (LDN) official Gene List. Results: The final LDSS comprised 4 major criteria and 10 minor criteria, with a cutoff of 2 major or 1 major and 3 minor criteria established to define LD. Interestingly, when applied to both the LDN list and a comprehensive gene list encompassing genes included in clinical panels and published as LFRD genes, we identified four genes (GRN, SLC29A3, CLN7 and VPS33A) absent from the LDN list, that were deemed associated with LD. Conversely, a subset of non-classic genes included in the LDN list, such as MTOR, OCRL, and SLC9A6, received lower LDSS scores for their associated disease entities. While these genes may not be suitable for inclusion in clinical LD multi-gene panels, they could be considered for inclusion on other, non-LD gene panels. Discussion: The LDSS offers a systematic approach to prioritize genes for clinical validity assessment. By identifying genes with high scores on the LDSS, this method enhanced the efficiency of gene curation by the ClinGen LD GCEP. Conclusion: The LDSS not only serves as a tool for gene prioritization prior to clinical validity curation, but also contributes to the ongoing discussion on the definition of LD. Moreover, the LDSS provides a flexible framework adaptable to future discoveries, ensuring its relevance in the ever-expanding landscape of LD research. Competing Interests: Declaration of competing interest D.B., H.C., C.H., R.M., and T.Y., are employed by laboratories offering free-for-service testing related to lysosomal diseases. L.C. is a paid consultant with Genzyme/Sanofi related to the MPS I (IDUA) registry. The other authors declare no conflicts of interest. (Copyright © 2024 Elsevier Inc. All rights reserved.) |
Databáze: | MEDLINE |
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