Low incidence of &lt;i&gt;EPOR&lt;/i&gt; mutations in idiopathic erythrocytosis

Filser, Mathilde; Aral, Bernard; Airaud, Fabrice; Chauveau, Aurélie; Bruce, Aisha; Polfrit, Yann; Thiébaut, Anne; Gauthier, Martin; Maréchal, Cédric Le; Lippert, Éric; Béziau, Stéphane; Garrec, Céline; Gardie, Betty; Girodon, François

doi:10.3324/haematol.2019.244160

Cited by 11 publications

(25 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In essence, EPO in synergy with several growth factors (SCF, GM-CSF, 1L-3, and IGF-1) enhances red cell survival by inhibition of apoptosis together with maturation and proliferation of erythroid progenitor cells. Germline heterozygous nonsense and frameshift mutations in exon 8 of EPOR have been described causing truncation of the C-terminal distal portion of the receptor which contains several tyrosine residues that serve as docking sites for SHP1, SOCS3 that are negative regulators of EPO signaling [14,[54][55][56]. This results in hypersensitivity to EPO via excessive activation of the EPO receptor [57][58][59].…”

Section: Epor Mutationmentioning

confidence: 99%

“…In a high proportion (70%) of patients with erythrocytosis, a specific etiology remains elusive despite extensive testing; such cases are often referred to as “idiopathic” or “not otherwise specified” [ 7 , 55 ]. In rare instances , SH2B3/LNK exon 2 mutations or polymorphisms have been reported in patients with unexplained erythrocytosis, with subnormal serum EPO levels, and absence of JAK2, MPL, and EPOR mutations [ 90 , 91 ].…”

Section: Diagnostic Approachmentioning

confidence: 99%

See 1 more Smart Citation

JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views

et al. 2021

View full text Add to dashboard Cite

JAK2 unmutated or non-polycythemia vera (PV) erythrocytosis encompasses both hereditary and acquired conditions. A systematic diagnostic approach begins with documentation of historical hematocrit (Hct)/hemoglobin (Hgb) measurements and classification of the process as life-long/unknown duration or acquired. Further investigation in both categories is facilitated by determination of serum erythropoietin level (EPO). Workup for hereditary/congenital erythrocytosis requires documentation of family history and laboratory screening for high-oxygen affinity hemoglobin variants, 2, 3 biphosphoglycerate deficiency, and germline mutations that are known to alter cellular oxygen sensing (e.g., PHD2, HIF2A, VHL) or EPO signaling (e.g., EPOR mutations); the latter is uniquely associated with subnormal EPO. Acquired erythrocytosis is often elicited by central or peripheral hypoxia resulting from cardiopulmonary disease/high-altitude dwelling or renal artery stenosis, respectively; EPO in the former instance is often normal (compensated by negative feed-back). Other conditions associated with acquired erythrocytosis include EPO-producing tumors and the use of drugs that promote erythropoiesis (e.g., testosterone, erythropoiesis stimulating agents). “Idiopathic erythrocytosis” loosely refers to an otherwise not explained situation. Historically, management of non-PV erythrocytosis has been conflicted by unfounded concerns regarding thrombosis risk, stemming from limited phenotypic characterization, save for Chuvash polycythemia, well-known for its thrombotic tendency. In general, cytoreductive therapy should be avoided and phlebotomy is seldom warranted where frequency is determined by symptom control rather than Hct threshold. Although not supported by hard evidence, cardiovascular risk optimization and low-dose aspirin use are often advised. Application of modern genetic tests and development of controlled therapeutic intervention trials are needed to advance current clinical practice.

show abstract

Section: Epor Mutationmentioning

confidence: 99%

Section: Diagnostic Approachmentioning

confidence: 99%

JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views

et al. 2021

View full text Add to dashboard Cite

show abstract

“…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%

“… 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%

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

Kristan

Pajič²,

Maver³

et al. 2021

Front. Genet.

View full text Add to dashboard Cite

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.

show abstract

“…2 In a recent study which included 270 patients with idiopathic erythrocytosis, 1.1% harbored EPOR mutations, while pathogenic variants involving genes in the hypoxia pathway were identified in 23% of patients. 3 Accordingly, we share the Mayo Clinic clinical and laboratory experience with hereditary erythrocytosis resulting from genetic alterations in the oxygen-sensing pathway (VHL-HIF2A-PHD2),…”

Section: To the Editormentioning

confidence: 99%

Erythrocytosis associated with EPAS1(HIF2A), EGLN1(PHD2), VHL, EPOR or BPGM mutations: The Mayo Clinic experience

et al. 2022

View full text Add to dashboard Cite

show abstract

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

Cited by 11 publications

References 18 publications

JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views

JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views

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

Erythrocytosis associated with <i>EPAS1</i>(<i>HIF2A</i>), <i>EGLN1</i>(<i>PHD2</i>), <i>VHL, EPOR</i> or <i>BPGM</i> mutations: The Mayo Clinic experience

Contact Info

Product

Resources

About