Gene Validity Classification Summary

Gene/Disease Pair:

DIAPH1 : diaph1-related sensorineural hearing loss-thrombocytopenia syndrome

HGNC:2876 | MONDO_0044635
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 7
Neuhaus C et al. 2017 Jun (PMID:27808407); Sommen M et al. 2016 Aug (PMID:27068579); Stritt S et al. 2016 Jun 9 (PMID:26912466); Lynch ED et al. 1997 Nov 14 (PMID:9360932);
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 3 3  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 23.18 1
Lynch ED et al. 1997 Nov 14 (PMID:9360932);
Total Summed LOD Score 23.18    
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) 10
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 2 0.5
Carreira S et al. 2006 Dec 15 (PMID:17182868); Li D et al. 2013 Mar (PMID:23325789);
Expression 0.5 0 - 2 1 0.5
Neuhaus C et al. 2017 Jun (PMID:27808407);
Functional Alteration Patient cells 1 0 - 2 2 1
0.5
1.5
Stritt S et al. 2016 Jun 9 (PMID:26912466);
Non-patient cells 0.5 0 - 1 2 1
Stritt S et al. 2016 Jun 9 (PMID:26912466); Ueyama T et al. 2016 Nov (PMID:27707755);
Models Non-human model organism 2 0 - 4 4 2 3.5 3.5
Cosetti M et al. 2008 Nov (PMID:19102128); Ueyama T et al. 2016 Nov (PMID:27707755);
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) 6

 


 

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 10 6 16 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
10/02/2018
EXPERT CURATION (DATE)
Definitive
01/05/2018
EVIDENCE SUMMARY
The DIAPH1 gene has been associated with autosomal dominant hearing loss and thrombocytopenia using the ClinGen Clinical Validity Framework as of 2/24/17. Families with segregations have been reported in the original paper in 1997 (Lynch et al.) and in three additional publications (27808407, 27068579, 26912466). The original paper did not report thrombocytopenia, though it can be subclinical and cannot be excluded from this family. All variants in these families have been LOF/truncating variants in exon 27. The mechanism for disease is not clear, but Ueyama 2016 provides evidence LOF is not a mechanism for hearing loss (27707755). Of note, LOF variants in other exons of this gene have been implicated in autosomal recessive microcephaly and seizures. This disease is not covered by the scope of this curation. In summary, DIAPH1 is definitively associated with autosomal dominant hearing loss and thrombocytopenia. 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 1/5/18.