Submission Details

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.