Gene Validity Curation

GATA2 - GATA2 deficiency with susceptibility to MDS/AML

Gene: GATA2 (HGNC:4171)
Classification - 08/18/2019
Disease: GATA2 deficiency with susceptibility to MDS/AML (MONDO_0042982)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hereditary Cancer EP
Evidence Summary: GATA2 was first reported in relation to autosomal dominant GATA2-deficiency with susceptibility to MDS/AML in 2011. This occurred over several publications, referring to the condition as Emberger Syndrome (Ostergaard et al., 2011 PMID 21892158), familial MDS (Hahn et al., 2011 PMID 21895162), DMCL (Dickinson et al., 2011 21765025), and MonoMac (Hsu et al., 2011 PMID 21670465). At least 40 variants (including missense, nonsense, frameshift, and large deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of Case Level Data: 12 points Variants in this gene have been reported in at least 19 probands in 7 publications (PMIDs: 21892158, 21895162, 21670465, 22147895, 23223431, 23502222, 25624456). Variants in this gene segregated with disease in 46 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is haploinsufficiency (Hsu et al., 2013 PMID 23502222). Summary of Experimental Evidence: 5 points This gene-disease association is supported by its biochemical function as part of the transcriptional program for blood (Gottgens et al., 2002 PMID 12065417), expression in hematopoietic cells (Kazenwadel et al., 2012 PMID 22147895), functional alteration in both patient and non-patient cells leading to altered gene expression (PMIDs: 21892162, 23502222, 25624456), and two mouse model organisms with limited utility due to lethality (PMIDs: 8078582, 22996665). In summary GATA2 is definitively associated with autosomal dominant GATA2-deficiency with susceptibility to MDS/AML. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms, inheritance pattern, or phenotypic variability underlying the disease entities: Emberger Syndrome (MIM 614038), Immunodeficiency 21 (MIM 614172), susceptibility to acute myeloid leukemia (MIM 601626) and susceptibility to Myelodysplastic syndrome (MIM 614286). Today it is well accepted that all these clinical manifestations belong to the broad spectrum of a single genetic disease; the term GATA2 deficiency or haploinsufficiency has been widely accepted to describe GATA2-related disorders (Wlodarski et al., 2017 PMID 28637621). Therefore, all of the disease entities have been lumped into one disease entity, dominant GATA2-deficiency with susceptibility to MDS/AML.
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 3
5.5
5.5
Kazenwadel J et al. 2012 Feb 2 (PMID:22147895); Pasquet M et al. 2013 Jan 31 (PMID:23223431);
Proband with predicted or proven null variant 1.5 0-2 10 5 7.5 7.5
Hsu AP et al. 2011 Sep 8 (PMID:21670465); Ostergaard P et al. 2011 Sep 4 (PMID:21892158); Pasquet M et al. 2013 Jan 31 (PMID:23223431);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 9
4.8
4.8
Hsu AP et al. 2011 Sep 8 (PMID:21670465); Hahn CN et al. 2011 Sep 4 (PMID:21892162); Kazenwadel J et al. 2012 Feb 2 (PMID:22147895); Pasquet M et al. 2013 Jan 31 (PMID:23223431); Hsu AP et al. 2013 May 9 (PMID:23502222); Cortés-Lavaud X et al. 2015 Mar 1 (PMID:25624456);
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 1.5 1.5  
Candidate gene sequencing 6.02 3
Ostergaard P et al. 2011 Sep 4 (PMID:21892158); Hahn CN et al. 2011 Sep 4 (PMID:21892162);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 6.02    
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 1
0.5
1
Göttgens B et al. 2002 Jun 17 (PMID:12065417);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Kazenwadel J et al. 2012 Feb 2 (PMID:22147895);
Functional Alteration Patient cells 1 0 - 2 2 1
1
2
Hsu AP et al. 2013 May 9 (PMID:23502222);
Non-patient cells 0.5 0 - 1 2 1
Hahn CN et al. 2011 Sep 4 (PMID:21892162); Cortés-Lavaud X et al. 2015 Mar 1 (PMID:25624456);
Models Non-human model organism 2 0 - 4 4 2 2 2
Tsai FY et al. 1994 Sep 15 (PMID:8078582); Lim KC et al. 2012 Oct (PMID:22996665);
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) 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 17 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
06/19/2019
EXPERT CURATION (DATE)
Definitive
08/18/2019
EVIDENCE SUMMARY
GATA2 was first reported in relation to autosomal dominant GATA2-deficiency with susceptibility to MDS/AML in 2011. This occurred over several publications, referring to the condition as Emberger Syndrome (Ostergaard et al., 2011 PMID 21892158), familial MDS (Hahn et al., 2011 PMID 21895162), DMCL (Dickinson et al., 2011 21765025), and MonoMac (Hsu et al., 2011 PMID 21670465). At least 40 variants (including missense, nonsense, frameshift, and large deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of Case Level Data: 12 points Variants in this gene have been reported in at least 19 probands in 7 publications (PMIDs: 21892158, 21895162, 21670465, 22147895, 23223431, 23502222, 25624456). Variants in this gene segregated with disease in 46 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is haploinsufficiency (Hsu et al., 2013 PMID 23502222). Summary of Experimental Evidence: 5 points This gene-disease association is supported by its biochemical function as part of the transcriptional program for blood (Gottgens et al., 2002 PMID 12065417), expression in hematopoietic cells (Kazenwadel et al., 2012 PMID 22147895), functional alteration in both patient and non-patient cells leading to altered gene expression (PMIDs: 21892162, 23502222, 25624456), and two mouse model organisms with limited utility due to lethality (PMIDs: 8078582, 22996665). In summary GATA2 is definitively associated with autosomal dominant GATA2-deficiency with susceptibility to MDS/AML. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms, inheritance pattern, or phenotypic variability underlying the disease entities: Emberger Syndrome (MIM 614038), Immunodeficiency 21 (MIM 614172), susceptibility to acute myeloid leukemia (MIM 601626) and susceptibility to Myelodysplastic syndrome (MIM 614286). Today it is well accepted that all these clinical manifestations belong to the broad spectrum of a single genetic disease; the term GATA2 deficiency or haploinsufficiency has been widely accepted to describe GATA2-related disorders (Wlodarski et al., 2017 PMID 28637621). Therefore, all of the disease entities have been lumped into one disease entity, dominant GATA2-deficiency with susceptibility to MDS/AML.