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. 2019 Oct;21(10):2239-2247.
doi: 10.1038/s41436-019-0487-0. Epub 2019 Mar 21.

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

Marina T DiStefano  1   2 , Sarah E Hemphill  1 , Andrea M Oza  1   3 , Rebecca K Siegert  2 , Andrew R Grant  2 , Madeline Y Hughes  2 , Brandon J Cushman  1 , Hela Azaiez  4 , Kevin T Booth  4   5 , Alex Chapin  6 , Hatice Duzkale  7 , Tatsuo Matsunaga  8   9 , Jun Shen  1   10 , Wenying Zhang  11 , Margaret Kenna  3   10 , Lisa A Schimmenti  12 , Mustafa Tekin  13 , Heidi L Rehm  1   2 , Ahmad N Abou Tayoun  14 , Sami S Amr  15   16 ; ClinGen Hearing Loss Clinical Domain Working Group
Collaborators, Affiliations

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

Marina T DiStefano et al. Genet Med. 2019 Oct.

Erratum in

  • Correction: ClinGen expert clinical validity curation of 164 hearing loss gene-disease pairs.
    DiStefano MT, Hemphill SE, Oza AM, Siegert RK, Grant AR, Hughes MY, Cushman BJ, Azaiez H, Booth KT, Chapin A, Duzkale H, Matsunaga T, Shen J, Zhang W, Kenna M, Schimmenti LA, Tekin M, Rehm HL, Tayoun ANA, Amr SS; ClinGen Hearing Loss Clinical Domain Working Group. DiStefano MT, et al. Genet Med. 2019 Oct;21(10):2409. doi: 10.1038/s41436-019-0553-7. Genet Med. 2019. PMID: 31114025

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.

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Figures

Figure 1:
Figure 1:
Gene curation workflow. A gene list was generated from 17 clinical testing labs present in the GTR. Nonsyndromic and syndromic genes with hearing loss as a presenting feature were prioritized and fully curated. Syndromic conditions were partially curated in Supplementary Table 2.
Figure 2:
Figure 2:
A. The clinical validity of 164 gene-disease pairs; Definitive= 82, Strong=12, Moderate=25, Limited=32, Disputed=10, Refuted= 3. B. Syndromic (N=59) and nonsyndromic (N=105) breakdown of 164 gene-disease pairs. C. Curations split by inheritance pattern; Autosomal Recessive (AR)=96, Autosomal Dominant (AD)=59, X-linked=7, Mitochondrial=2
Figure 3:
Figure 3:
Gene-disease pairs were plotted against the binned number (0–5, 6–9, 10–17) of Next Generation Sequence (NGS) panels on which they appear. These NGS panels were the 17 panels used to assemble a curation gene list per the methods. Genes that were linked with more than one disease were only plotted once with their highest classification. Total gene-disease pairs plotted on this graph N=142
Figure 4:
Figure 4:
ClinVar miner was used to pull all variants submitted with assertion criteria to ClinVar with the collection method “clinical testing”. If genes had a higher classification in addition to a Limited, Disputed, Refuted classification, only submissions linked to the Limited, Disputed, or Refuted disease entity were counted. Limited (N=25), Refuted (N=3), Disputed (N=10) gene-disease pairs.
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