Submission Details

FLI1 gene was first reported in relation to autosomal dominant bleeding disorder, platelet-type, 21 in 2013 (Stockley J, et al., PMID: 24100448). At least six unique variants (five missense, one frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least six probands in three publications (PMIDs: 24100448, 28255014, 28748566). In addition, Dr. Juliana Perez Botero contribute four independent cases from three families (personal communications, from Versiti Diagnostic Laboratory Cohort). Two patients (mother and the son) carry the c.892delA (p.Ser298fs) variant, which is not reported in the literature. The other two patients carry the c.1010G>A(p.Arg337Gln) and c.1028A>G (p.Tyr343Cys) respectively and these two variants have been reported before. Also, Dr. Kate Downes has contributed an independent case of a female born in 2006 who presented with Macrothrombocytopenia. The proband carries a truncating variant NM_002017.5(FLI1):c.946G>T (p.Glu316Ter), listed in ClinVar (ClinVar Record). In the test order form, ACTN1, FLNA, TUBB1, and MYH9 were considered as likely candidates. This gene-disease relationship is also supported by its expression evidence that FLI1 preferentially expresses in hematopoietic cells (PMID: 8439553) and functional alteration in both patient cells (PMID: 28255014) and non-patient cells(PMID: 28255014). Additionally, there are 2 FLI1 insufficient cell models, which are the induced-pluripotent stem cell (iPSC)–derived megakaryocytes (iMegs), generated from a patient with PTSx and iPSCs from a control line with a targeted heterozygous FLI1 knockout (FLI1 +/-), the authors showed that the heterozygous FLI1 loss resulted in the megakaryocyte and platelet defects. In addition, patients with deletions of 11q23 who were confirmed to be heterozygous for a deletion of the FLI1 gene presented with giant alpha-granules on peripheral blood smear and dysmegakaryopoiesis with many micromegakaryocytes on bone marrow examination. Clinical characteristics in addition to thrombocytopenia included mental retardation, facial dysmorphism, clinodactyly, and pyloric stenosis (PMID: 14597985) and these patients, with multi-gene deletions, were not considered within this gene-disease relationship though mouse models and iPSCs derived megakaryocytes (iMegs) suggested that the heterozygous loss of FLI gene was responsible for the dysmegakaryopoiesis in these patients (PubMed: 10981960, 28432223). In summary, there is moderate evidence to support this gene-disease relationship. This classification was originally approved by the ClinGen Hemostasis Thrombosis Gene Curation Expert Panel on April 28, 2021. This gene-disease relationship was reevaluated on September 06, 2023. As a result of this reevaluation, the classification did not change.