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Identification of Variants Associated With Rare Hematological Disorder Erythrocytosis Using Targeted Next-Generation Sequencing Analysis

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Title: Identification of Variants Associated With Rare Hematological Disorder Erythrocytosis Using Targeted Next-Generation Sequencing Analysis
Authors: Aleša Kristan, Tadej Pajič, Aleš Maver, Tadeja Režen, Tanja Kunej, Rok Količ, Andrej Vuga, Martina Fink, Špela Žula, Helena Podgornik, Saša Anžej Doma, Irena Preložnik Zupan, Damjana Rozman, Nataša Debeljak
Source: Frontiers in Genetics, Vol 12 (2021)
Publisher Information: Frontiers Media S.A., 2021.
Publication Year: 2021
Collection: LCC:Genetics
Subject Terms: NGS – next-generation sequencing, erythrocytosis, targeted panel sequencing, iron metabolism, diagnostics, rare disease (RD), Genetics, QH426-470
More Details: An erythrocytosis is present when the red blood cell mass is increased, demonstrated as elevated hemoglobin and hematocrit in the laboratory evaluation. Congenital predispositions for erythrocytosis are rare, with germline variants in several genes involved in oxygen sensing (VHL, EGLN1, and EPAS1), signaling for hematopoietic cell maturation (EPOR and EPO), and oxygen transfer (HBB, HBA1, HBA2, and BPGM) that were already associated with the eight congenital types (ECYT1–8). Screening for variants in known congenital erythrocytosis genes with classical sequencing approach gives a correct diagnosis for only up to one-third of the patients. The genetic background of erythrocytosis is more heterogeneous, and additional genes involved in erythropoiesis and iron metabolism could have a putative effect on the development of erythrocytosis. This study aimed to detect variants in patients with yet unexplained erythrocytosis using the next-generation sequencing (NGS) approach, targeting genes associated with erythrocytosis and increased iron uptake and implementing the diagnostics of congenital erythrocytosis in Slovenia. Selected 25 patients with high hemoglobin, high hematocrit, and no acquired causes were screened for variants in the 39 candidate genes. We identified one pathogenic variant in EPAS1 gene and three novel variants with yet unknown significance in genes EPAS1, JAK2, and SH2B3. Interestingly, a high proportion of patients were heterozygous carriers for two variants in HFE gene, otherwise pathogenic for the condition of iron overload. The association between the HFE variants and the development of erythrocytosis is not clearly understood. With a targeted NGS approach, we determined an actual genetic cause for the erythrocytosis in one patient and contributed to better management of the disease for the patient and his family. The effect of variants of unknown significance on the enhanced production of red blood cells needs to be further explored with functional analysis. This study is of great significance for the improvement of diagnosis of Slovenian patients with unexplained erythrocytosis and future research on the etiology of this rare hematological disorder.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 1664-8021
Relation: https://www.frontiersin.org/articles/10.3389/fgene.2021.689868/full; https://doaj.org/toc/1664-8021
DOI: 10.3389/fgene.2021.689868
Access URL: https://doaj.org/article/e2d1e10e99874627bc2743516f61c758
Accession Number: edsdoj.2d1e10e99874627bc2743516f61c758
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  Data: Identification of Variants Associated With Rare Hematological Disorder Erythrocytosis Using Targeted Next-Generation Sequencing Analysis
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  Data: <searchLink fieldCode="AR" term="%22Aleša+Kristan%22">Aleša Kristan</searchLink><br /><searchLink fieldCode="AR" term="%22Tadej+Pajič%22">Tadej Pajič</searchLink><br /><searchLink fieldCode="AR" term="%22Aleš+Maver%22">Aleš Maver</searchLink><br /><searchLink fieldCode="AR" term="%22Tadeja+Režen%22">Tadeja Režen</searchLink><br /><searchLink fieldCode="AR" term="%22Tanja+Kunej%22">Tanja Kunej</searchLink><br /><searchLink fieldCode="AR" term="%22Rok+Količ%22">Rok Količ</searchLink><br /><searchLink fieldCode="AR" term="%22Andrej+Vuga%22">Andrej Vuga</searchLink><br /><searchLink fieldCode="AR" term="%22Martina+Fink%22">Martina Fink</searchLink><br /><searchLink fieldCode="AR" term="%22Špela+Žula%22">Špela Žula</searchLink><br /><searchLink fieldCode="AR" term="%22Helena+Podgornik%22">Helena Podgornik</searchLink><br /><searchLink fieldCode="AR" term="%22Saša+Anžej+Doma%22">Saša Anžej Doma</searchLink><br /><searchLink fieldCode="AR" term="%22Irena+Preložnik+Zupan%22">Irena Preložnik Zupan</searchLink><br /><searchLink fieldCode="AR" term="%22Damjana+Rozman%22">Damjana Rozman</searchLink><br /><searchLink fieldCode="AR" term="%22Nataša+Debeljak%22">Nataša Debeljak</searchLink>
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  Data: An erythrocytosis is present when the red blood cell mass is increased, demonstrated as elevated hemoglobin and hematocrit in the laboratory evaluation. Congenital predispositions for erythrocytosis are rare, with germline variants in several genes involved in oxygen sensing (VHL, EGLN1, and EPAS1), signaling for hematopoietic cell maturation (EPOR and EPO), and oxygen transfer (HBB, HBA1, HBA2, and BPGM) that were already associated with the eight congenital types (ECYT1–8). Screening for variants in known congenital erythrocytosis genes with classical sequencing approach gives a correct diagnosis for only up to one-third of the patients. The genetic background of erythrocytosis is more heterogeneous, and additional genes involved in erythropoiesis and iron metabolism could have a putative effect on the development of erythrocytosis. This study aimed to detect variants in patients with yet unexplained erythrocytosis using the next-generation sequencing (NGS) approach, targeting genes associated with erythrocytosis and increased iron uptake and implementing the diagnostics of congenital erythrocytosis in Slovenia. Selected 25 patients with high hemoglobin, high hematocrit, and no acquired causes were screened for variants in the 39 candidate genes. We identified one pathogenic variant in EPAS1 gene and three novel variants with yet unknown significance in genes EPAS1, JAK2, and SH2B3. Interestingly, a high proportion of patients were heterozygous carriers for two variants in HFE gene, otherwise pathogenic for the condition of iron overload. The association between the HFE variants and the development of erythrocytosis is not clearly understood. With a targeted NGS approach, we determined an actual genetic cause for the erythrocytosis in one patient and contributed to better management of the disease for the patient and his family. The effect of variants of unknown significance on the enhanced production of red blood cells needs to be further explored with functional analysis. This study is of great significance for the improvement of diagnosis of Slovenian patients with unexplained erythrocytosis and future research on the etiology of this rare hematological disorder.
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