. 2025 May;27(5):101392.

doi: 10.1016/j.gim.2025.101392. Epub 2025 Feb 19.

ClinGen recuration of hearing loss-associated genes demonstrates significant changes in gene-disease validity over time

Kezang C Tshering¹, Marina T DiStefano², Andrea M Oza¹, Pamela Ajuyah¹, Ryan Webb¹, Enyonam Edoh¹, Ellie Broeren¹, Julie Ratliff¹, Vanessa Gitau¹, Kelley Paris¹, Amal Aburyyan³, John Alexander⁴, Victoria Albano⁵, Donglin Bai⁶, Kevin T A Booth⁷, Paula I Buonfiglio⁸, Cherine Charfeddine⁹, Viviana Dalamón⁸, Ignacio Del Castillo¹⁰, Miguel Angel Moreno-Pelayo¹⁰, Hatice Duzkale¹¹, Ben Dorshorst¹², Rabia Faridi¹³, Margaret Kenna⁵, Morag A Lewis¹⁴, Minjie Luo¹⁵, Yu Lu¹⁶, Rahma Mkaouar¹⁷, Tatsuo Matsunaga¹⁸, Kiyomitsu Nara¹⁸, Arti Pandya¹⁹, Shelby Redfield³, Isabelle Roux¹³, Lisa A Schimmenti²⁰, Isabelle Schrauwen²¹, Sherin Shaaban²², Jun Shen²³, Barbara Vona²⁴, Richard J Smith²⁵, Heidi L Rehm², Hela Azaiez²⁵, Ahmad N Abou Tayoun²⁶, Sami S Amr²⁷; ClinGen Hearing Loss Clinical Domain Working Group

Collaborators, Affiliations

Collaborators

ClinGen Hearing Loss Clinical Domain Working Group:
Ahmad Abou Tayoun, Alaa Koleilat, Alexander Chapin, Amal Aburayyan, Andrea Oza, Anne B Giersch, Arti Pandya, Barbara Vona, Ben Dorshorst, Byung Yoon Choi, Cherine Charfeddine, Cynthia Morton, Donglin Bai, Ellie Broeren, Enyonam Edoh, Guney Bademci, Haixian He, Hatice Duzkale, Heidi Rehm, Hela Azaiez, Hideki Mutai, Hongen Xu, Ignacio Del Castillo, Isabelle Roux, Isabelle Schrauwen, Jiale Xiang, John Alexander, Julie Ratliff, Jun Shen, Junyu Zhang, Kelley Paris, Kevin Booth, Kezang Tshering, Kiyomitsu Nara, Kok Siong Poon, Kristin Kernohan, Lauren Gallagher, Lilian Downie, Lisa Schimmenti, Makoto Hosoya, Margaret Kenna, Marina DiStefano, Matias Morin, Miguel Angel Moreno-Pelayo, Minjie Luo, Morag Lewis, Mustafa Tekin, Nanna D Rendtorff, Pamela Ajuyah Robertson, Paula Buonfiglio, Qiaoning Guan, Rabia Faridi, Rahma Mkaouar, Richard Smith, Ryan Webb, Sami Amr, Seda Nur Homurlu, Shelby Redfield, Sherin Shaaban, Shin-Ichi Usami, Shin-Ya Nishio, Tatsuo Matsunaga, Theru Sivakumaran, Thomas Friedman, Vanessa Gitau, Victoria Albano, Victoria Siu, Viviana Dalamon, Yu Lu, Zippi Brownstein, Zubair Ahmed

Affiliations

¹ The Broad Institute of MIT and Harvard, Cambridge, MA.
² The Broad Institute of MIT and Harvard, Cambridge, MA; Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge, MA.
³ Department of Medicine, University of Washington, Seattle, WA.
⁴ Myriad Women's Health, South San Francisco, CA.
⁵ Department of Otolaryngology & Communication Enhancement, Boston Children's Hospital, Boston, MA.
⁶ Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
⁷ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN; Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN.
⁸ Laboratorio de Fisiología y Genética de la Audición. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres" (INGEBI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
⁹ Laboratory of Biomedical Genomics and Oncogenetics, Institute Pasteur of Tunis, University of Tunis El Manar, Tunis, Tunisia; Université de la Manouba, Institut de Biotechnologie de Sidi-Thabet, Ariana, Tunisia.
¹⁰ Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III (CB06/07/0048; CIBERER-ISCIII), Madrid, Spain.
¹¹ Color Health, Burlingame, CA.
¹² Prevention Genetics, Marshfield, WI.
¹³ Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD.
¹⁴ Wolfson Sensory, Pain and Regeneration Centre, King's College London, London, United Kingdom.
¹⁵ Division of Genomic Diagnostics, The Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
¹⁶ Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, China.
¹⁷ Laboratory of Biomedical Genomics and Oncogenetics, Institute Pasteur of Tunis, University of Tunis El Manar, Tunis, Tunisia.
¹⁸ Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
¹⁹ Division of Genetics and Metabolism, Department of Pediatrics, UNC School of Medicine, Chapel Hill, NC.
²⁰ Departments of Clinical Genomics, Mayo Clinic Enterprise, Rochester, MN.
²¹ Department of Translational Neurosciences, University of Arizona College of Medicine Phoenix, Phoenix, AZ.
²² Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT; ARUP Laboratories, Salt Lake City, UT.
²³ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
²⁴ Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany; Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.
²⁵ Molecular Otolaryngology and Renal Research Laboratories (MORL), Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA.
²⁶ Genomics Center of Excellence, Al Jalila Children's Specialty Hospital, Dubai Health, Dubai, United Arab Emirates; Center for Genomic Discovery, Mohammed Bin Rashid University, Dubai Health, Dubai, United Arab Emirates.
²⁷ Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge, MA. Electronic address: samr@bwh.harvard.edu.

PMID: 39987489
PMCID: PMC12170156 (available on 2026-05-01)
DOI: 10.1016/j.gim.2025.101392

ClinGen recuration of hearing loss-associated genes demonstrates significant changes in gene-disease validity over time

Kezang C Tshering et al. Genet Med. 2025 May.

. 2025 May;27(5):101392.

doi: 10.1016/j.gim.2025.101392. Epub 2025 Feb 19.

Authors

Collaborators

ClinGen Hearing Loss Clinical Domain Working Group:
Ahmad Abou Tayoun, Alaa Koleilat, Alexander Chapin, Amal Aburayyan, Andrea Oza, Anne B Giersch, Arti Pandya, Barbara Vona, Ben Dorshorst, Byung Yoon Choi, Cherine Charfeddine, Cynthia Morton, Donglin Bai, Ellie Broeren, Enyonam Edoh, Guney Bademci, Haixian He, Hatice Duzkale, Heidi Rehm, Hela Azaiez, Hideki Mutai, Hongen Xu, Ignacio Del Castillo, Isabelle Roux, Isabelle Schrauwen, Jiale Xiang, John Alexander, Julie Ratliff, Jun Shen, Junyu Zhang, Kelley Paris, Kevin Booth, Kezang Tshering, Kiyomitsu Nara, Kok Siong Poon, Kristin Kernohan, Lauren Gallagher, Lilian Downie, Lisa Schimmenti, Makoto Hosoya, Margaret Kenna, Marina DiStefano, Matias Morin, Miguel Angel Moreno-Pelayo, Minjie Luo, Morag Lewis, Mustafa Tekin, Nanna D Rendtorff, Pamela Ajuyah Robertson, Paula Buonfiglio, Qiaoning Guan, Rabia Faridi, Rahma Mkaouar, Richard Smith, Ryan Webb, Sami Amr, Seda Nur Homurlu, Shelby Redfield, Sherin Shaaban, Shin-Ichi Usami, Shin-Ya Nishio, Tatsuo Matsunaga, Theru Sivakumaran, Thomas Friedman, Vanessa Gitau, Victoria Albano, Victoria Siu, Viviana Dalamon, Yu Lu, Zippi Brownstein, Zubair Ahmed

Affiliations

¹ The Broad Institute of MIT and Harvard, Cambridge, MA.
² The Broad Institute of MIT and Harvard, Cambridge, MA; Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge, MA.
³ Department of Medicine, University of Washington, Seattle, WA.
⁴ Myriad Women's Health, South San Francisco, CA.
⁵ Department of Otolaryngology & Communication Enhancement, Boston Children's Hospital, Boston, MA.
⁶ Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
⁷ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN; Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN.
⁸ Laboratorio de Fisiología y Genética de la Audición. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres" (INGEBI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
⁹ Laboratory of Biomedical Genomics and Oncogenetics, Institute Pasteur of Tunis, University of Tunis El Manar, Tunis, Tunisia; Université de la Manouba, Institut de Biotechnologie de Sidi-Thabet, Ariana, Tunisia.
¹⁰ Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III (CB06/07/0048; CIBERER-ISCIII), Madrid, Spain.
¹¹ Color Health, Burlingame, CA.
¹² Prevention Genetics, Marshfield, WI.
¹³ Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD.
¹⁴ Wolfson Sensory, Pain and Regeneration Centre, King's College London, London, United Kingdom.
¹⁵ Division of Genomic Diagnostics, The Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
¹⁶ Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, China.
¹⁷ Laboratory of Biomedical Genomics and Oncogenetics, Institute Pasteur of Tunis, University of Tunis El Manar, Tunis, Tunisia.
¹⁸ Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
¹⁹ Division of Genetics and Metabolism, Department of Pediatrics, UNC School of Medicine, Chapel Hill, NC.
²⁰ Departments of Clinical Genomics, Mayo Clinic Enterprise, Rochester, MN.
²¹ Department of Translational Neurosciences, University of Arizona College of Medicine Phoenix, Phoenix, AZ.
²² Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT; ARUP Laboratories, Salt Lake City, UT.
²³ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
²⁴ Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany; Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.
²⁵ Molecular Otolaryngology and Renal Research Laboratories (MORL), Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA.
²⁶ Genomics Center of Excellence, Al Jalila Children's Specialty Hospital, Dubai Health, Dubai, United Arab Emirates; Center for Genomic Discovery, Mohammed Bin Rashid University, Dubai Health, Dubai, United Arab Emirates.
²⁷ Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge, MA. Electronic address: samr@bwh.harvard.edu.

PMID: 39987489
PMCID: PMC12170156 (available on 2026-05-01)
DOI: 10.1016/j.gim.2025.101392

Erratum in

ClinGen recuration of hearing loss-associated genes demonstrates significant changes in gene-disease validity over time.
Tshering KC, DiStefano MT, Oza AM, Ajuyah P, Webb R, Edoh E, Broeren E, Ratliff J, Gitau V, Paris K, Aburyyan A, Alexander J, Albano V, Bai D, Booth KTA, Buonfiglio PI, Charfeddine C, Dalamón V, Castillo ID, Moreno-Pelayo MA, Duzkale H, Dorshorst B, Faridi R, Kenna M, Lewis MA, Luo M, Lu Y, Mkaouar R, Matsunaga T, Nara K, Pandya A, Redfield S, Roux I, Schimmenti LA, Schrauwen I, Shaaban S, Shen J, Vona B, Smith RJ, Rehm HL, Azaiez H, Abou Tayoun AN, Amr SS; ClinGen Hearing Loss Clinical Domain Working Group. Tshering KC, et al. Genet Med. 2025 Oct;27(10):101500. doi: 10.1016/j.gim.2025.101500. Epub 2025 Sep 7. Genet Med. 2025. PMID: 40923570 No abstract available.

Abstract

Purpose: The Clinical Genome Resource (ClinGen) Hearing Loss Gene Curation Expert Panel was assembled in 2016 and has since curated 174 gene-disease relationships (GDRs) using ClinGen's semiquantitative framework. ClinGen mandates the timely recuration of all GDRs classified as Disputed, Limited, Moderate, and Strong every 2 to 3 years.

Methods: Thirty-five GDRs met the criteria for recuration within 2 years of original curation. Previous evidence was reevaluated using the latest curation guidelines, and a comprehensive literature review was performed to obtain new evidence. Recurations were approved by the Gene Curation Expert Panel and published on the ClinGen website (www.clinicalgenome.org).

Results: Eight of 35 GDRs (22%) changed their classification. Two Moderate and 5 Strong GDRs were upgraded to Definitive because of new case evidence. One Strong was subsumed under another Definitive GDR after evaluation of the lumping/splitting of disease entities. Twenty-seven of 35 patients remained unchanged, with little to no new evidence reported.

Conclusion: Genes classified as Moderate and Strong were likely to build evidence and change their classification over time, whereas Limited were unlikely to gain evidence. These findings highlight the critical role of recuration in ensuring that genetic tests and research studies incorporate the most recent evidence into their efforts.

Keywords: ClinGen; Deafness; Gene curation; Genetic diagnosis; Hearing loss.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Many authors are compensated clinical service providers as noted by their affiliations in health care systems or commercial genetic testing laboratories. The authors declare no other relevant conflicts of interest.

References

1. Rehm HL, Berg JS, Brooks LD, et al. ClinGen--the Clinical Genome Resource. N Engl J Med. 2015;372(23):2235–2242. doi: 10.1056/NEJMsr1406261 - DOI - PMC - PubMed
1. Milko LV, Funke BH, Hershberger RE, et al. Development of Clinical Domain Working Groups for the Clinical Genome Resource (ClinGen): lessons learned and plans for the future. Genet Med. 2019;21(4):987–993. doi: 10.1038/s41436-018-0267-2 - DOI - PMC - PubMed
1. DiStefano MT, Hemphill SE, Oza AM, et al. ClinGen expert clinical validity curation of 164 hearing loss gene–disease pairs. Genetics in Medicine. 2019;21(10). doi: 10.1038/s41436-019-0487-0 - DOI - PMC - PubMed
1. Oza AM, DiStefano MT, Hemphill SE, et al. Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss. Hum Mutat. 2018;39(11):1593–1613. doi: 10.1002/humu.23630 - DOI - PMC - PubMed
1. Thaxton C, Goldstein J, DiStefano M, et al. Lumping versus splitting: How to approach defining a disease to enable accurate genomic curation. Cell Genomics. 2022;2(5). doi: 10.1016/j.xgen.2022.100131 - DOI - PMC - PubMed

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ClinGen recuration of hearing loss-associated genes demonstrates significant changes in gene-disease validity over time

Collaborators

Affiliations

ClinGen recuration of hearing loss-associated genes demonstrates significant changes in gene-disease validity over time

Authors

Collaborators

Affiliations

Erratum in

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous