Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

BCKDK : branched-chain keto acid dehydrogenase kinase deficiency

HGNC:16902 | MONDO_0013970
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Aminoacidopathy
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 4
7.5
7.75
Novarino G et al. 2012 Oct 19 (PMID:22956686); García-Cazorla A et al. 2014 Apr (PMID:24449431);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
0.25
Novarino G et al. 2012 Oct 19 (PMID:22956686);
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) 7.75
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
1
1
Harris RA et al. 1994 Aug (PMID:8064409);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
1
1.5
García-Cazorla A et al. 2014 Apr (PMID:24449431);
Non-patient cells 0.5 0 - 1 1 0.5
Oyarzabal A et al. 2016 Apr (PMID:26809120);
Models Non-human model organism 2 0 - 4 4 2 3 3.5
Zigler JS et al. 2016 July 29 (PMID:27472223); Joshi MA et al. 2006 Nov 15 (PMID:16875466);
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 1 0.5
García-Cazorla A et al. 2014 Apr (PMID:24449431);
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 7.75 6 13.75 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
01/06/2019
EXPERT CURATION (DATE)
Definitive
01/08/2019
EVIDENCE SUMMARY
BCKDK was first reported in relation to branched-chain keto acid dehydrogenase kinase deficiency, which is inherited in an autosomal recessive manner, in 2012 (Novarino et al, PMID 22956686). Evidence supporting this gene-disease relationship includes case-level and experimental data. Five unique variants (nonsense, frameshift, missense, and generation of a cryptic splice site) have been reported in in 8 individuals in 5 families (3 families each had 2 affected siblings) (Novarino et al, 2012, PMID 22956686; García-Cazorla et al, 2014, PMID 24449431). This gene-disease relationship is supported by the biochemical function of BCKDK, studies in fibroblasts from patients showing increased metabolism of branched chain alpha-keto acids, rescue of phosphorylation of E1-alpha in BCKDK-deficient fibroblasts upon expressing the wild type cDNA, a knock out mouse model (Joshi et al, 2006, PMID 16875466), and a natural rat model (Zigler et al, 2016, PMID 27472223). BCKDK negatively regulates the branched chain alpha-keto acid dehydrogenase (BCKD) complex by phosphorylating the E1-alpha subunit. As a result, the BCKD complex is constitutively active, resulting in the low levels of branched chain amino and alpha-keto acids observed in patients and animal models.