Gene panel sequencing improves the diagnostic work-up of patients with idiopathic erythrocytosis and identifies new mutations

Camps, Carlos; Petousi, Nayia; Bento, Celeste; Cario, Holger; Copley, Richard R.; McMullin, Mary Frances; Wijk, Richard van; Ratcliffe, Peter J.; Robbins, Peter A.; Taylor, Jenny C.

doi:10.3324/haematol.2016.144063

Cited by 69 publications

(114 citation statements)

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“…Whole exome sequencing is rapidly being implemented as a diagnostic tool for a wide spectrum of haematological diseases (Camps et al , 2016; Hansen et al , 2016; Leinoe et al , 2016; Zhang et al , 2016). Prompted by the diagnostic conundrum for the majority of IBD ‐ suspected patients, we adopted WES into the diagnostic strategy at our institutions.…”

Section: Discussionmentioning

confidence: 99%

Application of whole‐exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia

et al. 2017

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SummaryRare inherited bleeding disorders (IBD) are a common cause of bleeding tendency. To ensure a correct diagnosis, specialized laboratory analyses are necessary. This study reports the results of an upfront diagnostic strategy using targeted whole exome sequencing. In total, 156 patients with a significant bleeding assessment tool score participated in the study, of which a third had thrombocytopenia. Eighty‐seven genes specifically associated with genetic predisposition to bleeding were analysed by whole exome sequencing. Variants were classified according to the five‐tier scheme. We identified 353 germline variants. Eight patients (5%) harboured a known pathogenic variant. Of the 345 previously unknown variants, computational analyses predicted 99 to be significant. Further filtration according to the Mendelian inheritance pattern, resulted in 59 variants being predicted to be clinically significant. Moreover, 34% (20/59) were assigned as novel class 4 or 5 variants upon targeted functional testing. A class 4 or 5 variant was identified in 30% of patients with thrombocytopenia (14/47) versus 11% of patients with a normal platelet count (12/109) (P < 0·01). An IBD diagnosis has a major clinical impact. The genetic investigations detailed here extricated our patients from a diagnostic conundrum, thus demonstrating that continuous optimization of the diagnostic work‐up of IBD is of great benefit.

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Section: Discussionmentioning

confidence: 99%

Application of whole‐exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia

et al. 2017

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“…It was identified in two independent families with erythrocytosis and is sufficiently substantiated by segregation data to assume its disease causing effect, most probably due to increased EPO regulation . Three variants are located within exons 2 and 4 in patients with FE; however, the causative for FE needs to be confirmed. Pathogenic variant c.32delG located in exon 2 causative for FE was recently identified.…”

Section: Resultsmentioning

confidence: 95%

“…Out of 11 tested sequence variants of the EPO gene, seven were associated with erythrocytosis or upper‐limit hematocrit (Table ) . Four tested sequence variants were not associated with FE or clinical signs .…”

Section: Resultsmentioning

confidence: 99%

“…Erythrocytosis comprises a heterogeneous group of disorders characterized by the expansion of the erythrocyte compartment in the peripheral blood, clinically reflected by an increased hematocrit, hemoglobin or red blood cell (RBC) number . Erythrocytosis is classified as congenital or acquired and its mechanism may be primary or secondary …”

Section: Introductionmentioning

confidence: 99%

“…The erythropoietin receptor ( EPOR ) mutation is the indicator for primary FE type 1 (ECYT1), also known as congenital erythrocytosis (CE) or primary congenital familial polycythemia . Secondary erythrocytosis results from aberrant regulation of erythropoiesis promoting substances acting on hematopoietic progenitors, mainly EPO . Secondary congenital erythrocytosis is characterized by inappropriately normal or high serum EPO levels due to defects in the oxygen sensing pathway (ECYT2‐5) or variants effecting hemoglobin oxygen affinity (ECYT6‐7) (OMIM) .…”

Section: Introductionmentioning

confidence: 99%

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Genetic variants of erythropoietin (EPO) and EPO receptor genes in familial erythrocytosis

Vočanec

Prijatelj

Debeljak

et al. 2018

Int J Lab Hematology

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Objectives Erythrocytosis is characterized by the expansion of erythrocyte compartment including elevated red blood cell number, hematocrit, and hemoglobin content. Familial erythrocytosis (FE) is a congenital disorder with different genetic background. Type 1 FE is primary FE caused by mutation in erythropoietin receptor gene (EPOR). Type 2‐5 FE are secondary FEs caused by mutations of genes involved in oxygen sensing pathway important for erythropoietin (EPO) regulation. In the present study, we summarized associations between EPOR and EPO gene variations with development of FE and searched for genetic variants located within regulatory regions. Methods Publications reporting EPOR and EPO sequence variants associated with FE or clinical features of erythrocytosis were retrieved from PubMed and WoS. In silico, sequence reanalysis was performed using Ensembl genomic browser, release 89 to screen for variants located within regulatory regions. Results To date, 28 variants of the EPOR and seven variants of the EPO gene have been associated with erythrocytosis or upper hematocrit. Sequence variants were also found to be present within regulatory regions. Conclusions Role of variants in regulatory regions of the EPO gene should be further investigated.

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Disorders of red cells and platelets

2021

Blood Cells

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Gene panel sequencing improves the diagnostic work-up of patients with idiopathic erythrocytosis and identifies new mutations

Cited by 69 publications

References 44 publications

Application of whole‐exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia

Application of whole‐exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia

Genetic variants of erythropoietin (EPO) and EPO receptor genes in familial erythrocytosis

Disorders of red cells and platelets

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