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

Kezang C Tshering; Marina T DiStefano; Andrea M Oza; Pamela Ajuyah; Ryan Webb; Enyonam Edoh; Ellie Broeren; Julie Ratliff; Vanessa Gitau; Kelley Paris; Amal Aburyyan; John Alexander; Victoria Albano; Donglin Bai; Kevin T A Booth; Paula I Buonfiglio; Cherine Charfeddine; Viviana Dalamón; Ignacio Del Castillo; Miguel Angel Moreno-Pelayo; Hatice Duzkale; Ben Dorshorst; Rabia Faridi; Margaret Kenna; Morag A Lewis; Minjie Luo; Yu Lu; Rahma Mkaouar; Tatsuo Matsunaga; Kiyomitsu Nara; Arti Pandya; Shelby Redfield; Isabelle Roux; Lisa A Schimmenti; Isabelle Schrauwen; Sherin Shaaban; Jun Shen; Barbara Vona; Richard J Smith; Heidi L Rehm; Hela Azaiez; Ahmad N Abou Tayoun; Sami S Amr; ClinGen Hearing Loss Clinical Domain Working Group

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, Marina T DiStefano, Andrea M Oza, Pamela Ajuyah, Ryan Webb, Enyonam Edoh, Ellie Broeren, Julie Ratliff, Vanessa Gitau, Kelley Paris, Amal Aburyyan, John Alexander, Victoria Albano, Donglin Bai, Kevin T A Booth, Paula I Buonfiglio, Cherine Charfeddine, Viviana Dalamón, Ignacio Del Castillo, Miguel Angel Moreno-PelayoHatice Duzkale, Ben Dorshorst, Rabia Faridi, Margaret Kenna, Morag A Lewis, Minjie Luo, Yu Lu, Rahma Mkaouar, Tatsuo Matsunaga, Kiyomitsu Nara, Arti Pandya, Shelby Redfield, Isabelle Roux, Lisa A Schimmenti, Isabelle Schrauwen, Sherin Shaaban, Jun Shen, Barbara Vona, Richard J Smith, Heidi L Rehm, Hela Azaiez, Ahmad N Abou Tayoun, Sami S Amr, ClinGen Hearing Loss Clinical Domain Working Group

Department of Clinical Genetics

1 Citation (Scopus)

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.

Original language	English
Article number	101392
Journal	Genetics in medicine : official journal of the American College of Medical Genetics
Volume	27
Issue number	5
ISSN	1098-3600
DOIs	https://doi.org/10.1016/j.gim.2025.101392
Publication status	Published - May 2025

Keywords

Humans
Hearing Loss/genetics
Databases, Genetic
Genetic Predisposition to Disease
Genome, Human/genetics
Genetic Association Studies
Data Curation
Deafness
ClinGen
Gene curation
Genetic diagnosis
Hearing loss

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Tshering, K. C., DiStefano, M. T., Oza, A. M., Ajuyah, P., Webb, R., Edoh, E., Broeren, E., Ratliff, J., Gitau, V., Paris, K., Aburyyan, A., Alexander, J., Albano, V., Bai, D., Booth, K. T. A., Buonfiglio, P. I., Charfeddine, C., Dalamón, V., Castillo, I. D., ... ClinGen Hearing Loss Clinical Domain Working Group (2025). ClinGen recuration of hearing loss-associated genes demonstrates significant changes in gene-disease validity over time. Genetics in medicine : official journal of the American College of Medical Genetics, 27(5), Article 101392. https://doi.org/10.1016/j.gim.2025.101392

ClinGen recuration of hearing loss-associated genes demonstrates significant changes in gene-disease validity over time. / Tshering, Kezang C; DiStefano, Marina T; Oza, Andrea M et al.
In: Genetics in medicine : official journal of the American College of Medical Genetics, Vol. 27, No. 5, 101392, 05.2025.

Research output: Contribution to journal › Journal article › Research › peer-review

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 2025, 'ClinGen recuration of hearing loss-associated genes demonstrates significant changes in gene-disease validity over time', Genetics in medicine : official journal of the American College of Medical Genetics, vol. 27, no. 5, 101392. https://doi.org/10.1016/j.gim.2025.101392

@article{34644cb796d148cb8432187596ac10a1,

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

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 = "Humans, Hearing Loss/genetics, Databases, Genetic, Genetic Predisposition to Disease, Genome, Human/genetics, Genetic Association Studies, Data Curation, Deafness, ClinGen, Gene curation, Genetic diagnosis, Hearing loss",

author = "Tshering, \{Kezang C\} and DiStefano, \{Marina T\} and Oza, \{Andrea M\} and Pamela Ajuyah and Ryan Webb and Enyonam Edoh and Ellie Broeren and Julie Ratliff and Vanessa Gitau and Kelley Paris and Amal Aburyyan and John Alexander and Victoria Albano and Donglin Bai and Booth, \{Kevin T A\} and Buonfiglio, \{Paula I\} and Cherine Charfeddine and Viviana Dalam{\'o}n and Castillo, \{Ignacio Del\} and Moreno-Pelayo, \{Miguel Angel\} and Hatice Duzkale and Ben Dorshorst and Rabia Faridi and Margaret Kenna and Lewis, \{Morag A\} and Minjie Luo and Yu Lu and Rahma Mkaouar and Tatsuo Matsunaga and Kiyomitsu Nara and Arti Pandya and Shelby Redfield and Isabelle Roux and Schimmenti, \{Lisa A\} and Isabelle Schrauwen and Sherin Shaaban and Jun Shen and Barbara Vona and Smith, \{Richard J\} and Rehm, \{Heidi L\} and Hela Azaiez and \{Abou Tayoun\}, \{Ahmad N\} and Amr, \{Sami S\} and Rendtorff, \{Nanna Dahl\} and \{ClinGen Hearing Loss Clinical Domain Working Group\}",

year = "2025",

month = may,

doi = "10.1016/j.gim.2025.101392",

language = "English",

volume = "27",

journal = "Genetics in medicine : official journal of the American College of Medical Genetics",

issn = "1098-3600",

publisher = "Elsevier BV",

number = "5",

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TY - JOUR

T1 - ClinGen recuration of hearing loss-associated genes demonstrates significant changes in gene-disease validity over time

AU - Tshering, Kezang C

AU - DiStefano, Marina T

AU - Oza, Andrea M

AU - Ajuyah, Pamela

AU - Webb, Ryan

AU - Edoh, Enyonam

AU - Broeren, Ellie

AU - Ratliff, Julie

AU - Gitau, Vanessa

AU - Paris, Kelley

AU - Aburyyan, Amal

AU - Alexander, John

AU - Albano, Victoria

AU - Bai, Donglin

AU - Booth, Kevin T A

AU - Buonfiglio, Paula I

AU - Charfeddine, Cherine

AU - Dalamón, Viviana

AU - Castillo, Ignacio Del

AU - Moreno-Pelayo, Miguel Angel

AU - Duzkale, Hatice

AU - Dorshorst, Ben

AU - Faridi, Rabia

AU - Kenna, Margaret

AU - Lewis, Morag A

AU - Luo, Minjie

AU - Lu, Yu

AU - Mkaouar, Rahma

AU - Matsunaga, Tatsuo

AU - Nara, Kiyomitsu

AU - Pandya, Arti

AU - Redfield, Shelby

AU - Roux, Isabelle

AU - Schimmenti, Lisa A

AU - Schrauwen, Isabelle

AU - Shaaban, Sherin

AU - Shen, Jun

AU - Vona, Barbara

AU - Smith, Richard J

AU - Rehm, Heidi L

AU - Azaiez, Hela

AU - Abou Tayoun, Ahmad N

AU - Amr, Sami S

AU - ClinGen Hearing Loss Clinical Domain Working Group

A2 - Rendtorff, Nanna Dahl

PY - 2025/5

Y1 - 2025/5

N2 - 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.

AB - 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.

KW - Humans

KW - Hearing Loss/genetics

KW - Databases, Genetic

KW - Genetic Predisposition to Disease

KW - Genome, Human/genetics

KW - Genetic Association Studies

KW - Data Curation

KW - Deafness

KW - ClinGen

KW - Gene curation

KW - Genetic diagnosis

KW - Hearing loss

UR - https://www.scopus.com/pages/publications/105000262009

U2 - 10.1016/j.gim.2025.101392

DO - 10.1016/j.gim.2025.101392

M3 - Journal article

C2 - 39987489

SN - 1098-3600

VL - 27

JO - Genetics in medicine : official journal of the American College of Medical Genetics

JF - Genetics in medicine : official journal of the American College of Medical Genetics

IS - 5

M1 - 101392

ER -

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

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Keywords

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