Gene Validity Curation

BTD - biotinidase deficiency

Gene: BTD (HGNC:1122)
Classification - 02/10/2020
Disease: biotinidase deficiency (MONDO_0009665)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hearing Loss EP Contributors:
  • General Gene Curation
  • General GCEP
Evidence Summary: BTD and autosomal recessive Biotinidase Deficiency was reported in 1994 by Cole et al. (PMID: 7509806). Profound biotinidase deficiency is defined as less than 10% of mean normal serum enzyme activity; partial biotinidase deficiency is defined as between 10% and 30% of mean normal serumactivity (PMID: 26810761). Patients with Biotinidase deficiency are treated with biotin. At least 200 unique variants (missense, frameshift, nonsense etc.) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data, including an animal model. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In summary, BTD is definitively associated with autosomal recessive Biotinidase Deficiency. 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 General Gene Curation Working Group in collaboration with Hearing Loss Gene Curation Expert Panel on 9/25/19.
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
10.5
12
Wolf B et al. 2005 Apr (PMID:15776412); Tiar A et al. 2014 Feb 15 (PMID:23481307); Cowan TM et al. 2012 Aug (PMID:22698809); Canda E et al. 2018 Aug 28 (PMID:29995633); Hsu RH et al. 2019 Jan 7 (PMID:30616616);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
3
Wolf B et al. 2005 Apr (PMID:15776412); Cowan TM et al. 2012 Aug (PMID:22698809);
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
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
0
Non-patient cells 0.5 0 - 1 1 0
Liu Z et al. 2018 Mar (PMID:29359854);
Models Non-human model organism 2 0 - 4 4 1 2 2
Pindolia K et al. 2014 May (PMID:24630269);
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 12 2 14 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
02/10/2020
EXPERT CURATION (DATE)
Definitive
02/10/2020
EVIDENCE SUMMARY
BTD and autosomal recessive Biotinidase Deficiency was reported in 1994 by Cole et al. (PMID: 7509806). Profound biotinidase deficiency is defined as less than 10% of mean normal serum enzyme activity; partial biotinidase deficiency is defined as between 10% and 30% of mean normal serumactivity (PMID: 26810761). Patients with Biotinidase deficiency are treated with biotin. At least 200 unique variants (missense, frameshift, nonsense etc.) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data, including an animal model. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In summary, BTD is definitively associated with autosomal recessive Biotinidase Deficiency. 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 General Gene Curation Working Group in collaboration with Hearing Loss Gene Curation Expert Panel on 9/25/19.