Gene Validity Curation

ANKRD26 - thrombocytopenia 2

Gene: ANKRD26 (HGNC:29186)
Classification - 09/25/2019
Disease: thrombocytopenia 2 (MONDO_0008555)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: ANKRD26 was first reported in relation to autosomal dominant thrombocytopenia 2 in 2011 (Pippucci T, et al., PMID: 21211618). At least 20 unique variants (in the 5’UTR) have been reported in humans. Evidence supporting this gene disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 18 probands in 7 publications (PMIDs: 26175287, 23677566, 30747248, 28109976, 24030261, 21467542, 21211618). Variants in this gene segregated with disease in 38 additional family members. The mechanism of disease is proposed to be gain of function, not haploinsufficiency (PMIDs: 21211618, 24430186). This gene-disease relationship is supported by altered expression and function in patient cells during megakaryopoeisis and proplatelet formation, as well as the rescue of proplatelet formation in patient cells by shRNA knockdown (PMID 24430186). In summary ANKRD26 is definitively associated with autosomal dominant thrombocytopenia 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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 1
1
1
Ouchi-Uchiyama M et al. 2015 Dec (PMID:26175287);
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 18
7
7
Pippucci T et al. 2011 Jan 7 (PMID:21211618); Noris P et al. 2011 Jun 16 (PMID:21467542); Noris P et al. 2013 Sep 12 (PMID:24030261); Boutroux H et al. 2015 Oct (PMID:25902755); Averina M et al. 2017 Mar (PMID:28109976); Diep RT et al. 2019 Feb 12. (PMID:30747248); Ventz R et al. 2013 Jun (PMID:23677566);
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 5.66 2
Pippucci T et al. 2011 Jan 7 (PMID:21211618);
Total Summed LOD Score 5.66    
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) 11
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Bluteau D et al. 2014 Feb (PMID:24430186);
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Bluteau D et al. 2014 Feb (PMID:24430186);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1
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 1
Bluteau D et al. 2014 Feb (PMID:24430186);
Total Experimental Evidence Points (Maximum 6) 2.5

 


 

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 11 2.5 13.5 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
04/03/2019
EXPERT CURATION (DATE)
Definitive
09/25/2019
EVIDENCE SUMMARY
ANKRD26 was first reported in relation to autosomal dominant thrombocytopenia 2 in 2011 (Pippucci T, et al., PMID: 21211618). At least 20 unique variants (in the 5’UTR) have been reported in humans. Evidence supporting this gene disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 18 probands in 7 publications (PMIDs: 26175287, 23677566, 30747248, 28109976, 24030261, 21467542, 21211618). Variants in this gene segregated with disease in 38 additional family members. The mechanism of disease is proposed to be gain of function, not haploinsufficiency (PMIDs: 21211618, 24430186). This gene-disease relationship is supported by altered expression and function in patient cells during megakaryopoeisis and proplatelet formation, as well as the rescue of proplatelet formation in patient cells by shRNA knockdown (PMID 24430186). In summary ANKRD26 is definitively associated with autosomal dominant thrombocytopenia 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.