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
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DISCUSSION

In our patient, whole-exome sequencing revealed the presence of a heterozygous deletion of one guanine in exon 9 (c.1160delG), which was classified as a likely pathogenic variant leading to a frameshift in the RUNX1 protein. Pathogenic heterozygous variants in the RUNX1 gene represent an established cause of mild to moderate thrombocytopenia, functional and ultrastructural platelet defects, and predisposition to myelodysplastic syndrome, acute myeloid leukemia, and less frequently acute T-cell lymphoblastic leukemia. Pathogenic heterozygous variants in the RUNX1 gene show high penetrance with variable expressivity and anticipation [4]. The clinical presentation is highly variable, ranging from the mild and moderate bleeding tendency to symptoms suggestive of the proliferation of immature hematopoietic cells such as fatigue, shortness of breath, fever, infections, and bleeding. The lifelong risk for malignant hematological diseases is 44% and the average age of occurrence is 33 years [4]. The association of the c.1160delG variant with thrombocytopenia has not been described to date, but there is evidence to suggest its pathogenicity. Although the variant presumably does not lead to nonsense-mediated decay, at least 94 amino acids of the RUNX1 protein are expected to be lost with changes in the transactivational domain / inhibitory domain / VWRPY motif, and protein extension by an additional 113 amino acids. So far, other C-terminal variants with a shift in the reading frame have been described, some of which lead to a loss of transactivational ability and a dominant-negative effect [5,6,7]. Furthermore, the variant is not present in the control population of the gnomAD project and is compatible with the referral diagnosis. Consistent genotype-phenotype correlations have not been identified in the RUNX1 gene [8]. Due to the identified rare type of sequence variant, we performed a genotype-phenotype association analysis for all deletions in the RUNX1 gene recorded in the ClinVar database. The analysis showed that there is no genotype and phenotype correlation among the described deletions in the ClinVar database. The remaining two recorded changes in exon 9 of the RUNX1 gene clinically presented as RUNX1-FPDMM, which matches with the clinical picture of our patient. The variant was classified as likely pathogenic (evidence categories PVS1 STR, PM2) according to ACMG/ AMP standards and guidelines for the evaluation of sequence variants (Richards et al. 2015), modified by ACGS recommendations.

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