Gene Validity Curation

GFI1B - platelet-type bleeding disorder 17

Gene: GFI1B (HGNC:4238)
Classification - 11/27/2019
Disease: platelet-type bleeding disorder 17 (MONDO_0008553)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: GFI1B was first reported in relation to Platelet-type bleeding disorder-17 in 2013 (Stevenson et al., PMID: 23927492). At least 9 unique variants including missense, nonsense, frameshift and splice site variants have been reported in humans. The GFI1B transcription factor is a member of the GFI zinc (Zn)-finger transcriptional repressor family which plays a pivotal role in hematopoiesis. Platelet-type bleeding disorder-17 is characterized by macrothrombocytopenia, a heterogeneous reduction of platelet alpha-granules in some cases associated with reduction of delta-granules, red cell anisopoikilocytosis, and a variable bleeding tendency. A consistent feature of the disease is that platelets express on their surface CD34. GFI1B variants reported to date cluster in the Zn-finger domain, with only three variants reported outside of this region. Large part of the patients reported are heterozygous for GF1B variants, and thus Platelet-type bleeding disorder-17 is considered autosomal dominant. However, 3 homozygous GFI1B variants have been reported. In PMID 28041820 the proband is homozygous for the p.Leu262Pro variant, the parents are carriers and do not express any phenotype. In 31249973 and PMID 28550182 the same individual is described, a female homozygous for the p.Ser185LeufsTer3 variant. The proband belongs to a large family in which the members homozygous for the variant express the phenotype while the heterozygous are healthy. Finally, in PMID 25258084 a patient is described homozygous for the p.Cys168Phe variant. We do not have any information about family members but in the same paper a patient heterozygous for the same variant is reported. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 9.9 Points. 9 variants in this gene have been reported in 11 probands in 9 publications (PMIDs: 31249973, 25258084, 28041820, 27122003, 24325358, 28880435, 28550182, 23927492, 28439885). Summary of Experimental Data: 4.5 Points This gene-disease association is supported by mouse models and in vitro functional assays. mice with a megakaryocyte-specific Gfi1b deletion exhibit macrothrombocytopenia, megakaryocytic dysplasia and platelet defect reminiscent of GFI1B-related thrombocytopenia (PMIDs: 28082345, 11825872, 30894540). GFI1B is a transcription repressor and in HEK293T cells transfected with the wild-type GFI1B or mutant GFI1B the wild type GFI1B repressed expression of the reporter gene while the mutant was unable to repress this expression (PMID 27122003). Megakaryocytes differentiated from patients-derive iPSCs recapitulates the megakaryocyte defect of Platelet-type bleeding disorder-17 (PMID 28880435). In summary, GFI1B is definitively associated with Platelet-type bleeding disorder-17. 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
Proband with predicted or proven null variant 1.5 0-2 10 6 7.5 7.5
Stevenson WS et al. 2013 Nov (PMID:23927492); Monteferrario D et al. 2014 Jan 16 (PMID:24325358); Kitamura K et al. 2016 July (PMID:27122003); Ferreira CR et al. 2017 Mar (PMID:28041820); Andres O et al. 2018 Oct (PMID:31249973); Chen L et al. 2014 Sep 26 (PMID:25258084); Schulze H et al. 2017 Sep (PMID:28550182);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 5
0.6
0.6
Ferreira CR et al. 2017 Mar (PMID:28041820); Uchiyama Y et al. 2018 Jun (PMID:28439885); Rabbolini DJ et al. 2017 Nov (PMID:28880435); Chen L et al. 2014 Sep 26 (PMID:25258084);
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 1.8 1.8  
Candidate gene sequencing 8.41 2
Stevenson WS et al. 2013 Nov (PMID:23927492); Monteferrario D et al. 2014 Jan 16 (PMID:24325358);
Exome/genome or all genes sequenced in linkage region 1.81 1
Rabbolini DJ et al. 2017 Nov (PMID:28880435);
Total Summed LOD Score 10.22    
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) 9.9
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
0.5
Saleque S et al. 2002 Feb 1 (PMID:11825872);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
1
2
Rabbolini DJ et al. 2017 Nov (PMID:28880435);
Non-patient cells 0.5 0 - 1 2 1
Kitamura K et al. 2016 July (PMID:27122003); Shooshtarizadeh P et al. 2019 Mar 20 (PMID:30894540);
Models Non-human model organism 2 0 - 4 4 1 2 2
Beauchemin H et al. 2017 Mar (PMID:28082345);
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) 4.5

 


 

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 9.9 4.5 14.4 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
11/13/2019
EXPERT CURATION (DATE)
Definitive
11/27/2019
EVIDENCE SUMMARY
GFI1B was first reported in relation to Platelet-type bleeding disorder-17 in 2013 (Stevenson et al., PMID: 23927492). At least 9 unique variants including missense, nonsense, frameshift and splice site variants have been reported in humans. The GFI1B transcription factor is a member of the GFI zinc (Zn)-finger transcriptional repressor family which plays a pivotal role in hematopoiesis. Platelet-type bleeding disorder-17 is characterized by macrothrombocytopenia, a heterogeneous reduction of platelet alpha-granules in some cases associated with reduction of delta-granules, red cell anisopoikilocytosis, and a variable bleeding tendency. A consistent feature of the disease is that platelets express on their surface CD34. GFI1B variants reported to date cluster in the Zn-finger domain, with only three variants reported outside of this region. Large part of the patients reported are heterozygous for GF1B variants, and thus Platelet-type bleeding disorder-17 is considered autosomal dominant. However, 3 homozygous GFI1B variants have been reported. In PMID 28041820 the proband is homozygous for the p.Leu262Pro variant, the parents are carriers and do not express any phenotype. In 31249973 and PMID 28550182 the same individual is described, a female homozygous for the p.Ser185LeufsTer3 variant. The proband belongs to a large family in which the members homozygous for the variant express the phenotype while the heterozygous are healthy. Finally, in PMID 25258084 a patient is described homozygous for the p.Cys168Phe variant. We do not have any information about family members but in the same paper a patient heterozygous for the same variant is reported. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 9.9 Points. 9 variants in this gene have been reported in 11 probands in 9 publications (PMIDs: 31249973, 25258084, 28041820, 27122003, 24325358, 28880435, 28550182, 23927492, 28439885). Summary of Experimental Data: 4.5 Points This gene-disease association is supported by mouse models and in vitro functional assays. mice with a megakaryocyte-specific Gfi1b deletion exhibit macrothrombocytopenia, megakaryocytic dysplasia and platelet defect reminiscent of GFI1B-related thrombocytopenia (PMIDs: 28082345, 11825872, 30894540). GFI1B is a transcription repressor and in HEK293T cells transfected with the wild-type GFI1B or mutant GFI1B the wild type GFI1B repressed expression of the reporter gene while the mutant was unable to repress this expression (PMID 27122003). Megakaryocytes differentiated from patients-derive iPSCs recapitulates the megakaryocyte defect of Platelet-type bleeding disorder-17 (PMID 28880435). In summary, GFI1B is definitively associated with Platelet-type bleeding disorder-17. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.