Characterization of genetic variants in the &lt;i&gt;EGLN1/PHD2&lt;/i&gt; gene identified in a European collection of patients with erythrocytosis

Marine, Delamare; Roy, Amandine Le; Pacault, Mathilde; Schmitt, Loïc; Garrec, Céline; Maaziz, Nada; Myllykoski, Matti; Karaghiannis, Valéna; Aral, Bernard; Catherwood, Mark; Airaud, Fabrice; Mansour‐Hendili, Lamisse; Hoogewijs, David; Peroni, Edoardo; Idriss, Salam; Lesieur, Valentine; Caillaud, Amandine; Si‐Tayeb, Karim; Chariau, Caroline; Gaignerie, Anne; Rab, Minke A.E.; Haferlach, Torsten; Meggendorfer, Manja; Bézieau, Stéphane; Benetti, Andrea; Casadevall, Nicole; Hirsch, Pierre; Rosé, Christian; Wémeau, Mathieu; Galactéros, Frédéric; Cassinat, Bruno; Bellosillo, Beatríz; Bento, Celeste; Wijk, Richard van; Petrides, Petro E.; Randi, Maria Luigia; McMullin, Mary Frances; Koivunen, Peppi; Girodon, François; Gardie, Betty

doi:10.3324/haematol.2023.282913

Cited by 4 publications

(3 citation statements)

References 53 publications

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“…In 2 patients we observed EGLN1- p.Arg370Gly and p.Ile269Thr variants, the first considered of unknown significance and the second as pathogenic using the MobiDetails annotation platform. 19 …”

Section: Discussionmentioning

confidence: 99%

Coexistence of multiple gene variants in some patients with erythrocytoses

Benetti,

Bertozzi, PhD, MD,

Ceolotto

et al. 2024

Mediterr J Hematol Infect Dis

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Background: Erythrocytosis is a relatively common condition, however a large proportion of these patients (70%) remain without a clear etiologic explanation. Methods: We set up a targeted NGS panel for patients with erythrocytosis and 118 sporadic patients with idiopathic erythrocytosis were studied. Results: In 40 (34%) patients no variant was found while in 78 (66%) we identified at least one germinal variant; 55 patients (70.5%) had 1 altered gene, 18 (23%) had 2 alterations, and 5 (6.4%) had 3. An altered HFE gene was observed in 51 cases (57.1%), EGLN1 in 18 (22.6%) and EPAS1, EPOR, JAK2, and TFR2 variants in 7.7%, 10.3%, 11.5%, and 14.1% patients, respectively. In 23 patients (19.45%), more than 1 putative variant was found in multiple genes. Conclusions: Genetic variants in patients with erythrocytosis were detected in about 2/3 of our cohort. A NGS panel including more candidate genes should reduce the number of cases diagnosed as “idiopathic” erythrocytosis in whom a cause cannot yet be identified. It is known that HFE variants are common in idiopathic erythrocytosis. TFR2 alterations supports the existence of a relationship between genes involved in iron metabolism and impaired erythropoiesis. Some novel multiple variants were identified. Erythrocytosis appears to be often of multigenic nature.

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Section: Discussionmentioning

confidence: 99%

Coexistence of multiple gene variants in some patients with erythrocytoses

Benetti,

Bertozzi, PhD, MD,

Ceolotto

et al. 2024

Mediterr J Hematol Infect Dis

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“…Attempts to address this conundrum have accumulated in large collaborations facilitating in silico studies and further exploration of family studies. 43 Again, through collaborations, issues such as non-coding regions will be addressed. Currently many barriers exist for the inclusion of non-coding regions in the rare disease setting.…”

Section: Mutational Testing/next-generation Sequencing-congenital Ery...mentioning

confidence: 99%

Erythrocytosis: Diagnosis and investigation

Noumani,

Harrison,

McMullin

2024

Int J Lab Hematology

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An absolute erythrocytosis is present when the red cell mass is greater than 125% of the predicted. This is suspected when the hemoglobin or hematocrit is above the normal range. An erythrocytosis can be classified as primary or secondary and congenital or acquired. The commonest primary acquired disorder is polycythemia vera. The diagnostic criteria for PV have evolved over time and this is the main diagnosis managed in hematology clinics. There are a variety of rare congenital causes both primary and secondary. In particular in young patients and/or those with a family history a congenital cause is suspected. There remains a larger cohort with acquired erythrocytosis mainly with non‐hematological pathology. In order to explore for a cause of erythrocytosis, measurement of the erythropoietin level is a first step. A low erythropoietin level indicates a primary cause and a normal or elevated level indicates a secondary etiology. Further investigation is then dictated by initial findings and includes mutational testing with PCR and NGS for those in whom a congenital cause is suspected. Following this possibly bone marrow biopsy, scans, and further investigation as indicated by history and initial findings. Investigation is directed toward the identification of those with a hematological disorder which would be best managed following guidelines in hematology clinics and referral elsewhere in those for whom there are non‐hematological reasons for the elevated hemoglobin.

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“…It was not mentioned whether these patients were also taking low-dose aspirin. On the other hand, we recently reported two large series of EPAS1/HIF2 - and EGLN1/PHD2 -mutated patients with congenital erythrocytosis who had a low rate of thrombotic complications, 13 , 14 suggesting that the mechanisms of thrombosis in secondary congenital erythrocytosis are complex.…”

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confidence: 99%