Gene Validity Curation

GRHL2 - nonsyndromic genetic deafness

Gene: GRHL2 (HGNC:2799)
Classification - 05/01/2020
Disease: nonsyndromic genetic deafness (MONDO_0019497)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hearing Loss EP
Evidence Summary: GRHL2 was first associated with autosomal dominant non-syndromic hearing loss as early as 2002 (Peters et al., PMID: 12393799). At least 7 unique variants (frameshift, splice site, exon deletion) have been reported in humans. This association was made using case-level data, animal models, expression studies, and protein interaction studies. Association is seen in at least 8 probands in 5 publications and 2 ClinVar SCVs (PMIDs: 12393799, 23813623, 25342930, 27911912, 32048449, SCV000575569.4, SCV000344371.3). Variants in this gene segregated with disease in 16 additional family members (PMIDs: 12393799, 23813623, 32048449). The mechanism for disease is haploinsufficiency (PMID: 12393799, 23813623, 25342930). This gene-disease association is supported by a zebrafish transposon-mediated gene trap model and mRNA rescue, expression studies in the inner ear of mice, and protein interaction studies showing GRHL2's interaction with claudins. In summary, GRHL2 is definitively associated with autosomal dominant non-syndromic hearing loss.
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 4 5.5 5.5
Peters LM et al. 2002 Nov 1 (PMID:12393799); Vona B et al. 2013 Aug (PMID:23813623); Iwasa YI et al. 2016 Dec 2 (PMID:27911912); Wu D et al. 2020 Feb 12 (PMID:32048449);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
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 7.31 3
Peters LM et al. 2002 Nov 1 (PMID:12393799); Vona B et al. 2013 Aug (PMID:23813623); Wu D et al. 2020 Feb 12 (PMID:32048449);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 7.31    
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) 7
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
1.5
Protein Interaction 0.5 0 - 2 1 0.5
Han Y et al. 2011 Aug 15 (PMID:21610158);
Expression 0.5 0 - 2 2 1
Peters LM et al. 2002 Nov 1 (PMID:12393799); Hosoya M et al. 2016 Feb 26 (PMID:26915689);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 1 3
Han Y et al. 2011 Aug 15 (PMID:21610158);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Han Y et al. 2011 Aug 15 (PMID:21610158);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4.5

 


 

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 7 4.5 11.5 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
05/04/2020
EXPERT CURATION (DATE)
Definitive
05/01/2020
EVIDENCE SUMMARY
GRHL2 was first associated with autosomal dominant non-syndromic hearing loss as early as 2002 (Peters et al., PMID: 12393799). At least 7 unique variants (frameshift, splice site, exon deletion) have been reported in humans. This association was made using case-level data, animal models, expression studies, and protein interaction studies. Association is seen in at least 8 probands in 5 publications and 2 ClinVar SCVs (PMIDs: 12393799, 23813623, 25342930, 27911912, 32048449, SCV000575569.4, SCV000344371.3). Variants in this gene segregated with disease in 16 additional family members (PMIDs: 12393799, 23813623, 32048449). The mechanism for disease is haploinsufficiency (PMID: 12393799, 23813623, 25342930). This gene-disease association is supported by a zebrafish transposon-mediated gene trap model and mRNA rescue, expression studies in the inner ear of mice, and protein interaction studies showing GRHL2's interaction with claudins. In summary, GRHL2 is definitively associated with autosomal dominant non-syndromic hearing loss.