Impact of thrombocytopenia-associated c.-118C&gt;T and c.-140C&gt;G ANKRD26 5’UTR variants in three-generational pedigree
Creators: name: Trizuljak, Jakub
name: Likavcová, Paulína
name: Kozubík, Kateřina Staňo
name: Vrzalová, Zuzana
name: Hynšt, Jakub
name: Deissová, Tereza
name: Štika, Jiří
name: Radová, Lenka
name: Prudková, Marie
name: Vaculová, Jana
name: Blaháková, Ivona
name: Smejkal, Petr
name: Kamelander, Jan
name: Pospíšilová, Šárka
name: Doubek, Michael
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Medicine
subject: Genetics
subject: FOS: Biological sciences
subject: Environmental Sciences not elsewhere classified
subject: Mental Health
subject: Infectious Diseases
subject: FOS: Health sciences

description: Inherited thrombocytopenias (ITs) encompass a group of rare disorders characterized by diminished platelet count. Recent advancements have unveiled various forms of IT, with inherited thrombocytopenia 2 (THC2) emerging as a prevalent subtype associated with germline variants in the critical 5’ untranslated region of the <i>ANKRD26</i> gene. This region is crucial in regulating the gene expression of <i>ANKRD26</i>, particularly in megakaryocytes. THC2 is an autosomal dominant disorder presenting as mild-to-moderate thrombocytopenia with minimal symptoms, with an increased risk of myeloproliferative malignancies. In our study of a family with suspected IT, three affected individuals harbored the c.-118C&gt;T <i>ANKRD26</i> variant, while four healthy members carried the c.-140C&gt;G <i>ANKRD26</i> variant. We performed a functional analysis by studying platelet-specific <i>ANKRD26</i> gene expression levels using quantitative real-time polymerase-chain reaction. Functional analysis of the c.-118C&gt;T variant showed a significant increase in <i>ANKRD26</i> expression in affected individuals, supporting its pathogenicity. On the contrary, carriers of the c.-140C&gt;G variant exhibited normal platelet counts and no significant elevation in the <i>ANKRD26</i> expression, indicating the likely benign nature of this variant. Our findings provide evidence confirming the pathogenicity of the c.-118C&gt;T <i>ANKRD26</i> variant in THC2 and suggest the likely benign nature of the c.-140C&gt;G variant. What is the context? Inherited thrombocytopenias (ITs) are rare conditions characterized by low platelet counts. Inherited thrombocytopenia 2 (THC2) is caused by <i>ANKRD26</i> gene changes leading to increased <i>ANKRD26</i> expression as the main reason for subsequent thrombocytopenia. THC2 results in a mild-to-moderate decrease in platelet count and increases blood cancer risk. We focused on understanding two <i>ANKRD26</i> variants in a family with a history of thrombocytopenia. What is new? We conducted functional analysis to understand the effect of variants on platelet function and gene expression. We identified three thrombocytopenic family members as carriers of <i>ANKRD26</i> variant c.-118C&gt;T. This variant is linked to increased expression of the <i>ANKRD26</i> gene and confirmed as the likely cause of THC2. Another variant, c.-140C&gt;G, was present in four healthy family members. Although it was considered causal for THC2 in the past, our study suggests that the c.-140C&gt;G variant does not elevate <i>ANKRD26</i> expression and does not cause thrombocytopenia. What is the impact? Understanding the genetic and functional implications of <i>ANKRD26</i> gene variants is crucial for THC2 diagnosis and management. Our study emphasizes the necessity of conducting functional analyses to precisely evaluate the clinical significance of variants linked to inherited blood disorders. Carriers of the c.-118C&gt;T variant should undergo vigilant monitoring for THC2 and potential cancer development. Conversely, the c.-140C&gt;G variant does not pose a risk of THC2 or heightened cancer susceptibility.