Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

HSD17B4 : Perrault syndrome

HGNC:5213 | MONDO_0017312
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max 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
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
9.5
12
Pierce SB et al. 2010 Aug 13 (PMID:20673864); Lieber DS et al. 2014 Mar 6 (PMID:24602372); Amor DJ et al. 2016 Dec (PMID:27790638);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
2.5
McMillan HJ et al. 2012 Nov 22 (PMID:23181892); Lines MA et al. 2014 Mar 18 (PMID:24553428); Chen K et al. 2017 Aug 23 (PMID:28830375);
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
 
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total 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 Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 0.5
Nishio SY et al. 2017 May (PMID:28263850);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4
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) 0.5

 


 

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 12 0.5 12.5 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
05/30/2018
EXPERT CURATION (DATE)
Definitive
05/30/2018
EVIDENCE SUMMARY
The HSD17B4 gene has been associated with autosomal recessive Perrault syndrome using the ClinGen Clinical Validity Framework as of 1/10/2018. This association was made using case-level data only. At least 19 missense, nonsense, frameshift variants and splice-site variants have been reported in humans. HSD17B4 was first associated with this disease in humans as early as 2010 (Pierce et al.). Association was scored in at least 7 probands in 6 publications (20673864, 23181892, 24553428, 24602372, 28830375, 27790638). Perrault syndrome is characterized by ovarian dysgenesis in females and often azoospermia in males, as well as childhood to adult onset sensorineural hearing loss and ataxia. More severe types of DBP deficiency occur which cause severe phenotypes and infant mortality. That is outside the scope of this curation, but is important to note. Very little experimental evidence exists for HSD17B4 and Perrault syndrome. In summary, HSD17B4 is definitively associated with autosomal recessive Perrault syndrome.