Gene Validity Classification Summary

Gene/Disease Pair:

EYA4 : nonsyndromic genetic deafness

HGNC:3522 | 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 8.5 8.5
Huang A et al. 2015 May 12 (PMID:25963406); Hildebrand MS et al. 2007 Jul 15 (PMID:17568404); Wayne S et al. 2001 Feb 1 (PMID:11159937); Frykholm C et al. 2015 May 25 (PMID:25681523); van Beelen E et al. 2016 Jan-Feb (PMID:26331839);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 1
0.5
0.5
Tan M et al. 2014 Dec (PMID:25242383);
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 3 3  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 6.02 2
Tan M et al. 2014 Dec (PMID:25242383); van Beelen E et al. 2016 Jan-Feb (PMID:26331839);
Total Summed LOD Score 6.02    
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
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Matsuzaki S et al. 2018 Jan 1 (PMID:29054432);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 3 1.5 1.5
Depreux FF et al. 2008 Feb (PMID:18219393); Fan Y et al. 2016 Nov (PMID:27545760); Schönberger J et al. 2005 Apr (PMID:15735644);
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) 2

 


 

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 2 14 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
01/05/2018
EVIDENCE SUMMARY
The EYA4​ gene has been associated with autosomal dominant nonsyndromic hearing loss​ using the ClinGen Clinical Validity Framework as of 12/28/2017. This association was made using case-level data only. At least 7​ variants (missense, nonsense, frameshift) have been reported in humans. EYA4​ was first associated with this disease in humans as early as 2001 (Wayne et al.​). Association is seen in at least 7​ probands in 6​ publications (11159937, ​17568404, 25681523, 25963406, 25242383, 26331839). Variants in this gene segregated with disease in >70 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Of note, at least one patient and a zebrafish model have been reported with a cardiac phenotype (Schonberger et al. 2005, 15735644). This gene-disease association is supported by a mouse model and expression studies. In summary, EYA4​ is definitively associated with autosomal dominant nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss​ Working Group on 1/5/2018.