Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

NDUFS4 : Leigh syndrome

HGNC:7711 | MONDO_0009723
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Mitochondrial Diseases
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
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 6
13
12
Ortigoza-Escobar JD et al. 2016 May (PMID:27079373); Budde SM et al. 2003 (PMID:14765537); Lamont RE et al. 2017 Mar (PMID:27671926); Assereto S et al. 2014 Jul (PMID:24020637); Assouline Z et al. 2012 Jun (PMID:22326555); Bénit P et al. 2003 May (PMID:12616398);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
2
Protein Interaction 0.5 0 - 2 1 2
Zhu J et al. 2016 Aug 18 (PMID:27509854);
Expression 0.5 0 - 2 1 0.5
Uhlén M et al. 2015 Jan 23 (PMID:25613900);
Functional Alteration Patient cells 1 0 - 2 2 1
1.5
1.5
Ugalde C et al. 2004 Mar 15 (PMID:14749350);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 3 6 4
Kruse SE et al. 2008 Apr (PMID:18396137); Quintana A et al. 2012 Jul (PMID:22653057); Foriel S et al. 2018 Mar 27 (PMID:29590638);
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 12 6 18 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
04/08/2019
EXPERT CURATION (DATE)
Definitive
04/08/2019
EVIDENCE SUMMARY
The relationship between NDUFS4 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of February 11, 2019. 18 articles were reviewed. NDUFS4 was first reported in relation to autosomal recessive Leigh syndrome spectrum in 1998 (Van den Heuvel et al 1998 PMID: 9463323). At least 12 unique variants predicted to cause a loss of or reduced function of the protein have been reported in ClinVar, suggesting homozygous loss of function is the mechanism of disease for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 6 probands with Leigh syndrome spectrum in 6 publications (PMID 27079373, 14765537, 27671926, 24020637, 22326555, 12616398). This gene-disease association is supported by protein interaction, expression, alterations in patient cell lines, and animal models. In summary, there is definitive evidence to support the relationship between NDUFS4 and autosomal recessive Leigh syndrome spectrum. More than three years have elapsed from the first proposal of the association to reach a definitive classification. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 11, 2019 (SOP Version 6).