Gene Validity Classification Summary

Gene/Disease Pair:

KCNQ4 : nonsyndromic genetic deafness

HGNC:6298 | MONDO_0019497
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hearing Loss EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10 6 7.5 7.5
Coucke PJ et al. 1999 Jul (PMID:10369879); Hildebrand MS et al. 2008 Nov (PMID:18941426); Kamada F et al. 2006 Apr 5 (PMID:16596322); Wasano K et al. 2015 Aug 7 (PMID:26036578); Naito T et al. 2013 May 23 (PMID:23717403); Ishikawa K et al. 2014 Jun (PMID:24655070);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 7
3
3
Coucke PJ et al. 1999 Jul (PMID:10369879); Hildebrand MS et al. 2008 Nov (PMID:18941426); Wang H et al. 2014 Aug 12 (PMID:25116015); Huang B et al. 2017 Mar 24 (PMID:28340560);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 15.98 4
Coucke PJ et al. 1999 Jul (PMID:10369879); Kamada F et al. 2006 Apr 5 (PMID:16596322); Wang H et al. 2014 Aug 12 (PMID:25116015); Huang B et al. 2017 Mar 24 (PMID:28340560);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 15.98    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
1
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Beisel KW et al. 2000 Oct 20 (PMID:11042367); Wu C et al. 2014 Feb 20 (PMID:24555524);
Functional Alteration Patient cells 1 0 - 2 2
1.5
Non-patient cells 0.5 0 - 1 2 1.5
Kubisch C et al. 1999 Feb 5 (PMID:10025409); Gao Y et al. 2013 Jul (PMID:23750663);
Models Non-human model organism 2 0 - 4 4 1 3 3
Kharkovets T et al. 2006 Feb 8 (PMID:16437162);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 5.5

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 5.5 17.5 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
10/04/2018
EXPERT CURATION (DATE)
Definitive
11/21/2017
EVIDENCE SUMMARY
The KCNQ4 gene has been associated with autosomal dominant nonsyndromic hearing loss in at least 35 probands in at least 15 publications. 25 unique missense variants, 2 in-frame deletions, and 6 truncating variants have been reported in humans, and there is segregation evidence in many families (PMID: 10369879, 28340560, 18941426, 25116015, 16596322, 26036578, 23717403, 24655070). KCNQ4 was first associated with this disease in humans in 1999 (Coucke et al.). More than enough genetic evidence is available in the literature to reach the maximum score (12 pts.). The hearing loss in patients is progressive and predominantly high-frequency, however the phenotypic spectrum may be variable. The mechanism for disease is either haploinsufficiency or dominant-negative, which is strongly supported by experimental evidence. This gene-disease association is also supported by multiple mouse models, expression evidence, and in vitro functional assays (PMID: 11042367, 24555524, 10025409, 23750663, 16437162). In summary, KCNQ4 is definitively associated with autosomal dominant nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 11/21/2017.