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Genet Med. 2019 Mar 21. doi: 10.1038/s41436-019-0487-0. [Epub ahead of print]

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

Author information

1
Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, MA, USA.
2
The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
3
Dept. of Otolaryngology and Communication Enhancement, Boston Children's Hospital, Boston, MA, USA.
4
Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa Hospital and Clinics, Iowa City, IA, USA.
5
The Interdisciplinary Graduate Program in Molecular Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
6
ARUP Laboratories, Salt Lake City, UT, USA.
7
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
8
Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
9
Medical Genetics Center, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
10
Harvard Medical School, Boston, MA, USA.
11
The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
12
Department of Otorhinolaryngology, Clinical Genomics and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
13
John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
14
Al Jalila Children's Specialty Hospital, Al Jaddaf, Dubai, United Arab Emirates.
15
Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, MA, USA. samr@partners.org.
16
Harvard Medical School, Boston, MA, USA. samr@partners.org.

Abstract

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.

KEYWORDS:

ClinGen; deafness; gene curation; genetic diagnosis; hearing loss

PMID:
30894701
DOI:
10.1038/s41436-019-0487-0

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