Gene Validity Curation

DMXL2 - nonsyndromic genetic deafness

Gene: DMXL2 (HGNC:2938)
Classification - 02/06/2020
Disease: nonsyndromic genetic deafness (MONDO_0019497)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Hearing Loss EP
Evidence Summary: DMXL2 was reported in relation to autosomal dominant nonsyndromic hearing loss in 2016 (Chen et al., PMID: 27657680). At least 1 variant (missense) has been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 1 proband in 1 publication (PMID: 27657680). Variants in this gene segregated with disease in 10 additional family members. Of note, this gene has also been implicated in other diseases including neurodevelopmental disorders; these will be assessed separately. This gene-disease association is supported by animal models and expression studies (PMID: 27657680, 22875945). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.
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
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 1
0.5
0.5
Chen DY et al. 2016 Sep 22. (PMID:27657680);
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 2 2  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 4.33 1
Chen DY et al. 2016 Sep 22. (PMID:27657680);
Total Summed LOD Score 4.33    
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) 2.5
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
Chen DY et al. 2016 Sep 22. (PMID:27657680); Einhorn Z et al. 2012 Aug 08 (PMID:22875945);
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 1
Einhorn Z et al. 2012 Aug 08 (PMID:22875945);
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 2.5 2 4.5 NO
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)
Limited
02/06/2020
EXPERT CURATION (DATE)
Limited
02/06/2020
EVIDENCE SUMMARY
DMXL2 was reported in relation to autosomal dominant nonsyndromic hearing loss in 2016 (Chen et al., PMID: 27657680). At least 1 variant (missense) has been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 1 proband in 1 publication (PMID: 27657680). Variants in this gene segregated with disease in 10 additional family members. Of note, this gene has also been implicated in other diseases including neurodevelopmental disorders; these will be assessed separately. This gene-disease association is supported by animal models and expression studies (PMID: 27657680, 22875945). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.