Heterogeneous Landscape of RUNX1 Related Disorder: Four Families with Inherited Thrombocytopenias and Novel Genetic Variants in RUNX1 Associated to Relevant Clinical Complications

Background

Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) is a rare autosomal dominant disease with incomplete penetrance and variable expressivity. It is characterized by thrombocytopenia and/or platelet functional defects. Although bleeding tendency is usually mild to moderate, an important hallmark of FPD/AML is the increased risk of myeloid neoplasms, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The 2016 revision to the WHO classification system for myeloid neoplasms has incorporated a section on "myeloid neoplasms with germline predisposition" including RUNX1, ANKRD26 and ETV6 genes, among others. There is a great phenotypic heterogeneity and diagnosis is challenging due to specific test is not available. Now, high-throughput sequencing (HTS) is revolutionizing genetic diagnosis of human diseases, including platelet disorders and is extremely helpful to identify this disorder.

Aims

To assess the clinical, platelet phenotype and their genetic defect of 4 unrelated families with RUNX1 related thrombocytopenia (RUNX1 -RT) in our cohort of 82 consecutive unrelated probands with inherited platelet disorders (IPDs).

Methods

We studied 5 patients from 4 unrelated families presenting with lifelong thrombocytopenia with normal platelet size. Clinical records were reviewed and bleeding scored with ISTH-BAT. Platelet phenotyping included peripheral blood smear and platelet aggregation. Patients DNAs were analyzed by HTS using a 71-gene panel related to IPDs. Causative variants were elucidated after a workflow algorithm filter based in quality, consequence-damaging, minor allele frequency <0.05 and in silico prediction tools. Finally, variants were qualified according to guidelines of the American College of Medical Genetics and Genomics and Association for Molecular Pathology.

Results

The median age was 28 years old (1-54), median platelet counts was 90x10³/mm³ (35-108x10³/mm³) and bleeding score was 3 (2-5). Clinical and family history, and laboratory findings in these patients are shown in Figure 1. Family 1 (F1) showed an autosomal dominant thrombocytopenia (P1, P2, brother and their mother). In this family, a extremely history of hematologic malignancies are presented: one brother underwent to allogeneic transplant from unrelated donor due to a high-risk MDS del(7q) and one daughter of P1 died at the age of 13 years old due to a refractory AML. In F2, a lifelong thrombocytopenia, bleeding and family history of breast cancer was characteristic; but, in F3, only a lifelong thrombocytopenia was referred. Finally, P5 showed mental retardation, corpus callosum hypoplasia, facial and cardiac abnormalities and severe thrombocytopenia. HTS revealed three novel variants affected to RUNX1 (F1, P3 and P4) (Figure 1) and one sporadic germ line RUNX1 deletion involving chromosome 21q22, which, was confirmed by in-situ hybridization, resulting in RUNX1 haploinsufficiency. The missense variants affected to runt homology domain may lead to dominant-negative effects and were associated with higher propensity to develop AML, but it usually needed a second alteration associated, as occurs in our families (F1 and F2).

Conclusion

HTS facilitates genetic confirmation of FPD/AML diagnosis, and may help investigating phenotype-genotype relationships in this heterogeneous landscape. An earlier diagnosis of this disorder improves the genetic counselling and appropriate therapeutic management.

Funding

Gerencia Regional de Salud [GRS 1370/A/16]; ISCIII & Feder (PI14/01956), CIberer CB15/00055, Sociedad Española de Trombosis y Hemostasia.

Figure 1

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Figure 1

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