Gene panel sequencing in idiopathic erythrocytosis

Girodon, François; Airaud, Fabrice; Garrec, Céline; Bézieau, Stéphane; Gardie, Betty

doi:10.3324/haematol.2016.158337

Cited by 4 publications

(11 citation statements)

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“…Finally, because the detection of variants in the genes with high similarity of sequences such as HBA1 and HBA2 is challenging using NGS, we decided not to include HBB, HBA1 and HBA2 genes in our NGS panel. 8 …”

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confidence: 99%

Low incidence of <i>EPOR</i> mutations in idiopathic erythrocytosis

et al. 2020

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Low incidence of <i>EPOR</i> mutations in idiopathic erythrocytosis

et al. 2020

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“…Inadequate coverage in the first exon regions with high GC content is a common problem in the NGS approach, and usually other methods are applied to sufficiently sequence those regions (Chen et al, 2013). Another shortcoming of the applied method was the detection of variants in HBA1 and HBA2 genes, which was also observed by other researchers (Girodon et al, 2017;Filser et al, 2021). NGS, particularly read alignment for these two genes, is challenging, due to high sequence similarity.…”

Section: Discussionmentioning

confidence: 99%

“…However, the practice has been so far that only about 20–30% of patients received a proper diagnosis with screening for known variants associated with erythrocytosis. Therefore, the majority of patients remained idiopathic ( Bento et al, 2013 ; Camps et al, 2016 ; Girodon et al, 2017 ; Bento, 2018 ). This implicates that several other genes and mechanisms must be involved in the disease development.…”

Section: Introductionmentioning

confidence: 99%

“… Camps et al (2016) developed the erythrocytosis gene panel of 21 candidate genes, which are involved in key disease-driven pathways or were identified in prior WGS projects ( Taylor et al, 2015 ; Camps et al, 2016 ). Targeted NGS of erythrocytosis-associated genes was later also used by a French research group studying erythrocytosis ( Girodon et al, 2017 ; Filser et al, 2021 ), and erythrocytosis gene panels are gradually introduced into the routine clinical practice ( Gaspersic et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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

Kristan

Pajič²,

Maver³

et al. 2021

Front. Genet.

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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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“…In recent years, idiopathic erythrocytoses have been better described, thanks in part to the use of genomic sequencing tools [ 3 ]. However, despite the use of next generation sequencing (NGS), an etiology is only found in about 25% of idiopathic erythrocytosis cases [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Importance of Sequencing HBA1, HBA2 and HBB Genes to Confirm the Diagnosis of High Oxygen Affinity Hemoglobin

Filser

Gardie

Wémeau

et al. 2022

Genes

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High oxygen affinity hemoglobin (HOAH) is the main cause of constitutional erythrocytosis. Mutations in the genes coding the alpha and beta globin chains (HBA1, HBA2 and HBB) strengthen the binding of oxygen to hemoglobin (Hb), bringing about tissue hypoxia and a secondary erythrocytosis. The diagnosis of HOAH is based upon the identification of a mutation in HBA1, HBA2 or HBB in specialized laboratories. Phenotypic studies of Hb are also useful, but electrophoretic analysis can be normal in 1/3 of cases. The establishment of the dissociation curve of Hb can be used as another screening test, a shift to the left indicating an increased affinity for Hb. The direct measurement of venous P50 using a Hemox Analyzer is of great importance, but due to specific analytic conditions, it is only available in a few specialized laboratories. Alternatively, an estimated measurement of the P50 can be obtained in most of the blood gas analyzers on venous blood. The aim of our study was therefore to determine whether a normal venous P50 value could rule out HOAH. We sequenced the HBB, HBA1 and HBA2 genes of 75 patients with idiopathic erythrocytosis. Patients had previously undergone an exhaustive medical check-up after which the venous P50 value was defined as normal. Surprisingly, sequencing detected HOAH in three patients (Hb Olympia in two patients, and Hb St Nazaire in another). A careful retrospective examination of their medical files revealed that (i) one of the P50 samples was arterial; (ii) there was some air in another sample; and (iii) the P50 measurement was not actually done in one of the patients. Our study shows that in real life conditions, due to pre-analytical contingencies, a venous P50 value that is classified as being normal may not be sufficient to rule out a diagnosis of HOAH. Therefore, we recommend the systematic sequencing of the HBB, HBA1 and HBA2 genes in the exploration of idiopathic erythrocytosis.

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Gene panel sequencing in idiopathic erythrocytosis

Abstract: IF 6.671International audienc

Cited by 4 publications

References 3 publications

Low incidence of <i>EPOR</i> mutations in idiopathic erythrocytosis

Low incidence of <i>EPOR</i> mutations in idiopathic erythrocytosis

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

Importance of Sequencing HBA1, HBA2 and HBB Genes to Confirm the Diagnosis of High Oxygen Affinity Hemoglobin

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