Balkan Journal of Medical Genetics

A NOVEL LIKELY PATHOGENIC VARIANT IN THE RUNX1 GENE AS THE CAUSE OF CONGENITAL THROMBOCYTOPENIA
Despotović M1,*, Pereza N2, Peterlin B3, Ostojić S2, Golob B3, Maver A3, Roganović J4
*Corresponding Author: Marta Despotović, University of Rijeka, Faculty of Medicine, Braće Branchetta 20, 51000 Rijeka, Croatia. Tel: +385-91-732-6486. E-mail: despotovicmarta@gmail.com
page: 4

INTRODUCTION

Thrombocytopenia is a condition characterized by decreased platelet counts in peripheral blood below 150 x 109/L, associated with an increased risk of bleeding predominantly into the skin and mucous membranes. It is classified as congenital and acquired. Causal factors for the development of congenital thrombocytopenia are sequence variants in genes encoding transcription factors important for megakaryocyte differentiation, platelet formation, or release [1]. According to the Human Phenotype Ontology database, 328 genes associated with thrombocytopenia have been described until now, among which the most common are RUNX1 (Runt-related Transcription Factor 1), ETV6 (ETS Variant Transcription Factor 6), and ANKRD26 (Ankyrin Repeat Domain 26). Pathogenic sequence variants in these genes can cause specific syndromes such as TAR (Thrombocytopenia-absent radius) syndrome, Wiskott-Aldrich syndrome, Bernard-Soulier syndrome, Gray platelet syndrome, and Alport syndrome. The first family with chronic thrombocytopenia and thrombocytopathy in childhood was described in 1978. Three of the ten siblings in this family died of myeloproliferative neoplasms [2]. This is considered the first described case of RUNX1 familial platelet disorder with associated myeloid malignancies (RUNX1-FPDMM). The RUNX1 gene encodes a protein of the same name, which is a transcription factor responsible for controlling hematopoiesis. Heterozygous pathogens and likely pathogenic sequence variants in the RUNX1 gene are often present in patients with decreased platelet count and/or dysfunction and are an indicator of the increased risk of developing myelodysplasia and acute myeloid leukemia. The most common causal variants are point mutations that lead to missense, nonsense, or frameshifts changes in the RUNX1 protein. Also, several large deletions and gene duplications have been described [3]. To date, 16 likely pathogenic and 27 pathogenic deletions of the RUNX1 gene have been described in the ClinVar database. Only two variants of unclear significance were described in exon 9, one substitution and one deletion. The aim of this paper is to present a patient with congenital thrombocytopenia caused by a rare variant in the RUNX1 gene, a heterozygous frameshift deletion, which is likely a de novo variant.

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