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AlphaMissense versus laboratory-based pathogenicity prediction of 13 novel missense CPA1 variants from pancreatitis cases
  1. Máté Sándor1,
  2. Isabelle Scheers2,
  3. Atsushi Masamune3,
  4. Heiko Witt4,
  5. Jessica LaRusch5,
  6. Jian-Min Chen6,
  7. Balázs Csaba Németh7,8,
  8. Andrea Geisz9,
  9. Aliye Uc10,
  10. Miklós Sahin-Tóth1
  1. 1Department of Surgery, University of California Los Angeles, Los Angeles, California, USA
  2. 2Department of Pediatric Gastroenterology and Hepatology, Cliniques universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
  3. 3Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
  4. 4Paediatric Nutritional Medicine, Else Kröner-Fresenius Zentrum für Ernährungsmedizin (EKFZ), Technische Universität München (TUM), Freising, Germany
  5. 5Ariel Precision Medicine, Pittsburgh, Pennsylvania, USA
  6. 6Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France
  7. 7Center for Gastroenterology, Department of Medicine, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
  8. 8Hungarian Centre of Excellence for Molecular Medicine, Translational Pancreatology Research Group, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
  9. 9Department of Surgery, Boston University, Boston, Massachusetts, USA
  10. 10Stead Family Department of Pediatrics and Department of Radiation Oncology, University of Iowa, Iowa City, Iowa, USA
  1. Correspondence to Dr Miklós Sahin-Tóth, Department of Surgery, University of California Los Angeles, Los Angeles, California, USA; msahintoth{at}mednet.ucla.edu

https://doi.org/10.1136/gutjnl-2024-333697

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    We have read with great interest the study by Wang et al1 in which the authors evaluated the utility of the AlphaMissense prediction programme2 (https://alphamissense.hegelab.org) in the classification of missense CPA1 variants with respect to pathogenicity in chronic pancreatitis. While the AI-driven prediction performed relatively well, the authors highlighted potential shortcomings that can limit its value in clinical practice. Defining the pathogenic potential of CPA1 variants detected in pancreatitis cases can be challenging because the mechanistic basis of disease risk is unrelated to loss of CPA1 function and seems to be determined by mutation-induced misfolding and the ensuing endoplasmic reticulum (ER) stress.3–5 Recently, we used transiently transfected HEK 293T cells to measure the secretion efficiency and induction of BiP mRNA expression, a marker of ER stress, for 50 missense CPA1 variants from pancreatitis cases and healthy controls.6 We found that the best predictor of pathogenicity was loss of secretion (<10% of wild type) irrespective of BiP levels. This data set can serve as a reference for the assignment of clinical significance of novel CPA1 variants. In the present study, we set out to examine what fraction of novel CPA1 variants detected in real-world genetic testing can be classified as pathogenic and whether AlphaMissense can replace …

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    Footnotes

    • Collaborators Anthony Raizis (Canterbury Health Laboratories, Christchurch, New Zealand), Kazuhiro Kikuta, Tetsuya Takikawa, Ryotaro Matsumoto, Shin Hamada, Hitomi Nakasuji (Tohoku University Graduate School of Medicine, Sendai, Japan), Nicole Revencu (Center for Human Genetics, Cliniques universitaires Saint-Luc, Brussels, Belgium), Cécile Libioulle (Laboratory of Molecular Genetics, CHU Liège, Brussels, Belgium), Péter Hegyi (Semmelweis University, Budapest, Hungary), Emmanuelle Masson (Univ Brest, Inserm, EFS, UMR 1078, GGB; CHRU Brest, Brest, France).

    • Contributors Study concept and design: MS-T. Experiments: IS, AM, HW, JL, J-MC, BCN and AU contributed genetic data, MS performed the functional assays with help from AG. Acquisition, analysis or interpretation of data: all authors. Drafting of the manuscript: MS-T. Critical revision of the manuscript for important intellectual content: all authors. Obtained funding: MS-T. Administrative, technical or material support: all authors. Study supervision: MS-T. Final approval of manuscript as submitted: all authors. Guarantor of the article: MS-T.

    • Funding This study was supported by the National Institutes of Health (NIH) grants R01 DK117809 and R01 DK082412 to MS-T, grants U01 DK108334 and R01 DK118752 to AU, and he EU's Horizon 2020 Research and Innovation Program under grant agreement No. 739593 to BCN.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; internally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.