ClinGen expert clinical validity curation of 164 hearing loss gene–disease pairs

Purpose Proper interpretation of genomic variants is critical to successful medical decision making based on genetic testing results. A fundamental prerequisite to accurate variant interpretation is the clear understanding of the clinical validity of gene–disease relationships. The Clinical Genome R...

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Published inGenetics in medicine Vol. 21; no. 10; pp. 2239 - 2247
Main Authors DiStefano, Marina T., Hemphill, Sarah E., Oza, Andrea M., Siegert, Rebecca K., Grant, Andrew R., Hughes, Madeline Y., Cushman, Brandon J., Azaiez, Hela, Booth, Kevin T., Chapin, Alex, Duzkale, Hatice, Matsunaga, Tatsuo, Shen, Jun, Zhang, Wenying, Kenna, Margaret, Schimmenti, Lisa A., Tekin, Mustafa, Rehm, Heidi L., Tayoun, Ahmad N. Abou, Amr, Sami S.
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.10.2019
Subjects
Biomedical and Life Sciences
Biomedicine
Data Curation - methods
Databases, Genetic
Deafness - genetics
Genetic Testing - methods
Genetic Testing - standards
Genetic Variation
Genome, Human
Genomics - methods
Hearing Loss - genetics
Human Genetics
Humans
Laboratory Medicine
Mutation
Reproducibility of Results
genetic diagnosis
hearing loss
deafness
ClinGen
gene curation
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Summary:Purpose Proper interpretation of genomic variants is critical to successful medical decision making based on genetic testing results. A fundamental prerequisite to accurate variant interpretation is the clear understanding of the clinical validity of gene–disease relationships. The Clinical Genome Resource (ClinGen) has developed a semiquantitative framework to assign clinical validity to gene–disease relationships. Methods The ClinGen Hearing Loss Gene Curation Expert Panel (HL GCEP) uses this framework to perform evidence-based curations of genes present on testing panels from 17 clinical laboratories in the Genetic Testing Registry. The HL GCEP curated and reviewed 142 genes and 164 gene–disease pairs, including 105 nonsyndromic and 59 syndromic forms of hearing loss. Results The final outcome included 82 Definitive (50%), 12 Strong (7%), 25 Moderate (15%), 32 Limited (20%), 10 Disputed (6%), and 3 Refuted (2%) classifications. The summary of each curation is date stamped with the HL GCEP approval, is live, and will be kept up-to-date on the ClinGen website ( https://search.clinicalgenome.org/kb/gene-validity ). Conclusion This gene curation approach serves to optimize the clinical sensitivity of genetic testing while reducing the rate of uncertain or ambiguous test results caused by the interrogation of genes with insufficient evidence of a disease link.
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These authors contributed equally to this effort
ClinGen Hearing Loss Clinical Domain Working group: Sonia Abdelhak, PhD, John Alexander, PhD, Karen Avraham, PhD, Neha Bhatia, MD, Donglin Bai, PhD, Nicole Boczek, PhD, Zippora Brownstein, PhD, Rachel Burt, PhD, Yasmin Bylstra, FHGSA, Ignacio del Castillo, PhD, Byung Yoon Choi, PhD, Lilian Downie, PhD, Thomas Friedman, PhD, Anne Giersch, PhD, Jasmine Goh, BSN, John Greinwald, MD, Andrew J. Griffith, MD, PhD, Amy Hernandez, MS, CGC, Jeffrey Holt, PhD, Makoto Hosoya, MD, PhD, Lim Jiin Ying, MS, CGC, Kanika Jain, Un-Kyung Kim, PhD, Hannie Kremer, PhD, Ian Krantz, MD, Suzanne Leal, PhD, Morag Lewis, PhD, Xue Zhong Liu, MD, PhD, Wendy Low, BS, MS, Yu Lu, Minjie Luo, PhD, Saber Masmoudi, PhD, Tan Yuen Ming, PhD, Miguel Angel Moreno-Pelayo, PhD, Matías Morín, PhD, Cynthia Morton, PhD, Jaclyn Murray, PhD, Hideki Mutai, PhD, Kiyomitsu Nara, PhD, Arti Pandya, MD, MBA, Sylvia Kam Pei-Rong, MS, CGC Richard J.H. Smith, MD, Saumya Shekhar Jamuar, MD, Funda Elif Suer, PhD, Shin-Ichi Usami, MD, PhD, Guy Van Camp, PhD, Kazuki Yamazawa, MD, PhD, Hui-Jun Yuan, PhD, Elizabeth Black-Zeigelbein, and Keijan Zhang, MD, MBA.
ISSN:1098-3600
1530-0366
DOI:10.1038/s41436-019-0487-0