• Evaluation of enzyme activity...

Treffer: Evaluation of enzyme activity predictions for variants of unknown significance in Arylsulfatase A.

Title:
Evaluation of enzyme activity predictions for variants of unknown significance in Arylsulfatase A.
Authors:
Jain S; The Institute for Experiential AI, Northeastern University, Boston, MA, USA.; Khoury College of Computer Sciences, Northeastern University, Boston, MA, USA., Trinidad M; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, USA., Nguyen TB; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia., Jones K; Tuskegee University, Tuskegee, AL, USA., Neto SD; Universidad Nacional de Rosario, Rosario, Argentina., Ge F; State Key Laboratory of Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), Nanjing University of Posts & Telecommunications, Nanjing, China., Glagovsky A; National University of Tucuman, Tucuman, Argentina., Jones C; Tuskegee University, Tuskegee, AL, USA., Moran G; University of Puerto Rico, San Juan, PR, USA., Wang B; Department of Bioinformatics and System Biology, University of California, San Diego, La Jolla, CA, USA., Rahimi K; Department of Computational Biology, School of Life Sciences, Ochanomizu University, Tokyo, Japan., Çalıcı SZ; Department of Genomics, Faculty of Aquatic Science, Istanbul University, Istanbul, Turkey., Cedillo LR; University of Texas at El Paso, El Paso, USA., Berardelli S; Department of Electrical, Computer, and Biomedical Engineering, University of Pavia, Pavia, Italy.; enGenome srl, Pavia, Italy., Özden B; Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Istanbul Kültür University, Istanbul, Turkey., Chen K; University of California, Berkeley, Berkeley, CA, USA., Katsonis P; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Williams A; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Lichtarge O; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Rana S; TCS Research, Mumbai, India., Pradhan S; TCS Research, Mumbai, India., Srinivasan R; TCS Research, Mumbai, India., Sajeed R; TCS Research, Mumbai, India., Joshi D; TCS Research, Mumbai, India., Faraggi E; Research and Information Systems LLC, Indianapolis, IN, USA.; Physics Department, Indiana University-Purdue University, Indianapolis, IN, USA., Jernigan R; Roy J. Carver Department of Biochemistry, Iowa State University, Ames, IA, USA., Kloczkowski A; Institute for Genomic Medicine, The Research Institute at Nationwide Children'S Hospital, Columbus, OH, USA., Xu J; University of California, Berkeley, Berkeley, CA, USA., Song Z; Peking University, Beijing, China., Özkan S; Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.; Universitat Autònoma de Barcelona, Barcelona, Spain., Padilla N; Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.; Universitat Autònoma de Barcelona, Barcelona, Spain., de la Cruz X; Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.; Universitat Autònoma de Barcelona, Barcelona, Spain.; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain., Acuna-Hidalgo R; Nostos Genomics GmbH, Berlin, Germany., Grafmüller A; Nostos Genomics GmbH, Berlin, Germany., Barrón LTJ; Nostos Genomics GmbH, Berlin, Germany., Manfredi M; Biocomputing Group, University of Bologna, Bologna, Italy., Savojardo C; Biocomputing Group, University of Bologna, Bologna, Italy., Babbi G; Biocomputing Group, University of Bologna, Bologna, Italy., Martelli PL; Biocomputing Group, University of Bologna, Bologna, Italy., Casadio R; Biocomputing Group, University of Bologna, Bologna, Italy., Sun Y; Department of Electrical & Computer Engineering, Texas a&M University, College Station, TX, USA., Zhu S; Department of Electrical & Computer Engineering, Texas a&M University, College Station, TX, USA., Shen Y; Department of Electrical & Computer Engineering, Texas a&M University, College Station, TX, USA., Pucci F; Computational Biology and Bioinformatics, Université Libre de Bruxelles, Bruxelles, Belgium., Rooman M; Computational Biology and Bioinformatics, Université Libre de Bruxelles, Bruxelles, Belgium., Cia G; Computational Biology and Bioinformatics, Université Libre de Bruxelles, Bruxelles, Belgium., Raimondi D; ESAT-STADIUS, Katholieke Universiteit Leuven, Leuven, Belgium., Hermans P; Computational Biology and Bioinformatics, Université Libre de Bruxelles, Bruxelles, Belgium., Kwee S; University of California, Berkeley, Berkeley, CA, USA., Chen E; University of California, Berkeley, Berkeley, CA, USA., Astore C; San Diego, CA, USA., Kamandula A; Khoury College of Computer Sciences, Northeastern University, Boston, MA, USA., Pejaver V; Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Ramola R; Khoury College of Computer Sciences, Northeastern University, Boston, MA, USA., Velyunskiy M; Khoury College of Computer Sciences, Northeastern University, Boston, MA, USA., Zeiberg D; Khoury College of Computer Sciences, Northeastern University, Boston, MA, USA., Mishra R; Department of Bioengineering, University of California, Berkeley, CA, USA.; Department of Bioengineering, University of California, San Francisco, CA, USA., Sterling T; San Anselmo, CA, USA., Goldstein JL; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Lugo-Martinez J; Ray and Stephanie Lane Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA., Kazi S; Houston, TX, USA., Li S; University of California, Berkeley, Berkeley, CA, USA., Long K; University of California, Berkeley, Berkeley, CA, USA., Brenner SE; University of California, Berkeley, Berkeley, CA, USA., Bakolitsa C; University of California, Berkeley, Berkeley, CA, USA., Radivojac P; Khoury College of Computer Sciences, Northeastern University, Boston, MA, USA., Suhr D; MLD Foundation, West Linn, OR, USA., Suhr T; MLD Foundation, West Linn, OR, USA., Clark WT; Hoosier Bulk Transport, Greens Fork, IN, USA. wyatt.travis.clark@gmail.com.
Source:
Human genetics [Hum Genet] 2025 Mar; Vol. 144 (2-3), pp. 295-308. Date of Electronic Publication: 2025 Mar 08.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Springer Verlag Country of Publication: Germany NLM ID: 7613873 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-1203 (Electronic) Linking ISSN: 03406717 NLM ISO Abbreviation: Hum Genet Subsets: MEDLINE
Imprint Name(s):
Publication: Berlin : Springer Verlag
Original Publication: Berlin, New York, Springer-Verlag.
MeSH Terms:
Cerebroside-Sulfatase*/genetics , Cerebroside-Sulfatase*/metabolism , Cerebroside-Sulfatase*/chemistry , Genetic Variation*, Humans ; Machine Learning ; Mutation, Missense
Comments:
Update of: bioRxiv. 2024 Jun 17:2024.05.16.594558. doi: 10.1101/2024.05.16.594558.. (PMID: 38798479)
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Grant Information:
U01 HG012022 United States HG NHGRI NIH HHS; U01HG012022 National Institutes of Health, United States; U24 HG007346 United States HG NHGRI NIH HHS; AG068214 National Institutes of Health, United States; U01 AG068214 United States AG NIA NIH HHS; R35 GM124952 United States GM NIGMS NIH HHS; R35GM124952 National Institutes of Health, United States; PID2019-11217RB-I00 Spanish Minesterio de Ciencia e Innocavion; U24HG007346 National Institutes of Health, United States; R01 HG012117 United States HG NHGRI NIH HHS; R01HG012117 National Institutes of Health, United States
Substance Nomenclature:
EC 3.1.6.8 (Cerebroside-Sulfatase)
Entry Date(s):
Date Created: 20250307 Date Completed: 20250511 Latest Revision: 20250531
Update Code:
20250531
PubMed Central ID:
PMC12122056
DOI:
10.1007/s00439-025-02731-3
PMID:
40055237
Database:
MEDLINE

Weitere Informationen

Continued advances in variant effect prediction are necessary to demonstrate the ability of machine learning methods to accurately determine the clinical impact of variants of unknown significance (VUS). Towards this goal, the ARSA Critical Assessment of Genome Interpretation (CAGI) challenge was designed to characterize progress by utilizing 219 experimentally assayed missense VUS in the Arylsulfatase A (ARSA) gene to assess the performance of community-submitted predictions of variant functional effects. The challenge involved 15 teams, and evaluated additional predictions from established and recently released models. Notably, a model developed by participants of a genetics and coding bootcamp, trained with standard machine-learning tools in Python, demonstrated superior performance among submissions. Furthermore, the study observed that state-of-the-art deep learning methods provided small but statistically significant improvement in predictive performance compared to less elaborate techniques. These findings underscore the utility of variant effect prediction, and the potential for models trained with modest resources to accurately classify VUS in genetic and clinical research.
(© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Declarations. Conflict of interest: Wyatt T. Clark, Marena Trinidad, Courtney Astore, Teague Sterling, and Sufyan Kazi are former employees and potential shareholders of BioMarin Pharmaceutical. Rocio Acuna-Hidalgo is a current employee and shareholder of Nostos Genomics GmbH. Andrea Grafmüller and Laura T. Jiménez Barrón are former employees of Nostos Genomics GmbH. Ethics approval: Not relevant. Consent to participate: Not relevant. Consent for publication: All authors have consented to publication of this manuscript.