| 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 |
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Genetic Evidence
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Case-Level Data
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Evidence Type | Case Information Type | Guidelines | Points | PMIDs/Notes | |||||
| Default | Range | Max | Count | Total | Counted | ||||||
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Variant Evidence
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Autosomal Dominant or X-linked Disorder | Variant is de novo | 2 | 0-3 | 12 |
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| 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);
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| Proband with other variant type with some evidence of gene impact | 0.5 | 0-1.5 | 7 | 1 |
0.5
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0.5 |
Tan M et al. 2014 Dec (PMID:25242383);
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| Autosomal Recessive Disease | Two variants in trans and at least one de novo or a predicted/proven null variant | 2 | 0-3 | 12 |
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| 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); |
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| Total Summed LOD Score | 6.02 | ||||||||||
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Case-Control Data
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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 |
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| Aggregate Variant Analysis | 0-6 |
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| Total Genetic Evidence Points (Maximum 12) | 12 |
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Experimental Evidence
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Evidence Category | Evidence Type | Guidelines | Points | PMIDs/Notes | ||||||
| Default | Range | Max | Count | Total | Counted | ||||||
| Function | Biochemical Function | 0.5 | 0 - 2 | 2 |
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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);
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| Functional Alteration | Patient cells | 1 | 0 - 2 | 2 |
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| 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);
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| Cell culture model | 1 | 0 - 2 | |||||||||
| Rescue | Rescue in human | 2 | 0 - 4 |
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| 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 |
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| 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)*
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| CALCULATED CLASSIFICATION (DATE) |
Definitive
10/04/2018
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| EXPERT CURATION (DATE) |
Definitive
01/05/2018
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| 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.
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