Gene Validity Classification Summary

Gene/Disease Pair:

RUNX1 : hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome

HGNC:10471 | MONDO_0011071
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hereditary Cancer EP
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 7.5 7.5
Song WJ et al. 1999 Oct (PMID:10508512); Michaud J et al. 2002 Feb 15 (PMID:11830488);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
2
2
Song WJ et al. 1999 Oct (PMID:10508512); Michaud J et al. 2002 Feb 15 (PMID:11830488);
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 Evidence of segregation in one or more families   Sequencing Method 0-3 3
3
3  
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
Song WJ et al. 1999 Oct (PMID:10508512);
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
1.5
Liakhovitskaia A et al. 2014 Sep (PMID:25139854);
Protein Interaction 0.5 0 - 2 0.5
Warren AJ et al. 2000 Jun 15 (PMID:10856244);
Expression 0.5 0 - 2 0.5
Lorsbach RB et al. 2004 Apr 1 (PMID:14630789);
Functional Alteration Patient cells 1 0 - 2 2
1
1
Song WJ et al. 1999 Oct (PMID:10508512);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 3
Ichikawa M et al. 2004 Mar (PMID:14966519);
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
Connelly JP et al. 2014 Sep 18 (PMID:25114263);
Total Experimental Evidence Points (Maximum 6) 5.5

 


 

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 5.5 17.5 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
06/04/2018
EVIDENCE SUMMARY
There has been sufficient amount of evidence published associating the RUNX1 gene with familial platelet disorder with associated myeloid malignancy (FPDMM) since the gene-disease relationship was first proposed by Song et al. (1999). Plenty of case level studies have been performed with FPDMM patients that have variants in the RUNX1 gene. RUNX1 has a primary role in the development of all hematopoietic cell types and RUNX1 is shown to express in hematopoietic lineages and peripheral lymphocytes. CBFB, the beta subunit forming the same transcriptional complex, is also associated with somatic acute myeloid leukemia. Megakaryocyte colony formation decreased in patient cells and targeted correction of RUNX1 rescue megakaryopoietic defects. Thrombocytopenia and megakaryocytic maturation arrest are reported in induced RUNX1 knockout mice. All of these evidences suggest a definitive relationship between the RUNX1 gene and familial platelet disorder with associated myeloid malignancy (FPDMM).