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

CASE REPORT

A one-month-old male infant was admitted to the Department of Pediatrics, Clinical Hospital Center Rijeka, due to anemia and thrombocytopenia verified during an acute viral infection. The father was treated for acute lymphoblastic leukemia in childhood, and at the age of 30 for thyroid cancer. Father and sister suffer from atopic diseases. In the first hospitalization, the patient received a red blood cell transfusion, followed by erythropoietin beta for six weeks. During follow-up, he occasionally had petechiae and ecchymoses on the lower extremities after mild trauma, with no other symptoms. Bone malformations have not been identified. He had normal values of erythrocytes and hemoglobin, occasionally mild neutropenia, persistently slightly decreased values of platelets that were normal morphology, but impaired functions - pathological aggregation with adrenaline and adenosine diphosphate (ADP). Glanzmann’s thrombasthenia and Bernard Soulier’s syndrome were ruled out. Specific platelet antibodies were negative several times, and on one occasion indirect antineutrophil antibodies were positive. Bone marrow aspiration showed impaired hematopoiesis, especially erythropoiesis and some hypolobulated megakaryocytes. At the age of 18 months, the boy had the first episode of typical febrile convulsions. At 20 months he was hospitalized for recurrent febrile convulsions and bilateral pleuropneumonia complicated by sepsis and hemolyticuremic syndrome. He was treated with the combination of parenteral antimicrobial therapy and irradiated red blood cell and platelet transfusions. At the age of two, he was hospitalized for Candida pelliculosa sepsis and treated with parenteral antifungals, intravenous immunoglobulins due to transient hypogammaglobulinemia, and granulocyte colony-stimulating factor due to severe neutropenia. Comprehensive immunological testing did not reveal an immune disorder. Repeated bone marrow aspiration was normal. At the same age, he underwent allergy skin testing because of atopic dermatitis, but the causative allergen was not found. After the second year of life, the boy did not have any serious infections and was regularly monitored on an outpatient basis. Physical and mental development was normal. Due to the unclear etiology of persistent mild thrombocytopenia, he was referred for genetic testing at the age of five. Genomic DNA was isolated from the patient’s peripheral blood and whole-exome sequencing was performed using next-generation sequencing, which included the analysis of 34 genes associated with the clinical presentation. Sequencing was performed using Illumina NovaSeq 6000. The analysis included sequencing of coding regions of genes defined based on prominent clinical presentation, as well as regions on the intron-exon boundary that may result in changes/defects in splicing. A heterozygous variant was identified in the RUNX1 gene (c.1160delG deletion of one guanine, NM_001754.4). The variant leads to a frameshift at the 387th position of the amino acid sequence encoded by RUNX1. The variant is located in exon 9 and was not described in the genome of 138,000 controls in the gnomAD project or the ClinVar database of clinically relevant variants. By ACMG/AMP standards and guidelines for the interpretation of sequence variants (Richards et al. 2015), modified by ACGS recommendations, the variant was classified as likely pathogenic (evidence categories PVS1_STR, PM2).

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