Format

Send to

Choose Destination
Haematologica. 2016 Nov;101(11):1306-1318. Epub 2016 Sep 20.

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

Author information

1
National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Oxford, UK.
2
Wellcome Trust Centre for Human Genetics, University of Oxford, UK.
3
Nuffield Department of Medicine, University of Oxford, UK nayia.petousi@ndm.ox.ac.uk.
4
Hematology Department, Centro Hospitalar e Universitário de Coimbra, Portugal.
5
Department of Pediatrics and Adolescent Medicine, University Medical Center, Ulm, Germany.
6
Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK.
7
Nuffield Department of Medicine, University of Oxford, UK.
8
Department of Physiology, Anatomy and Genetics, University of Oxford, UK.

Abstract

Erythrocytosis is a rare disorder characterized by increased red cell mass and elevated hemoglobin concentration and hematocrit. Several genetic variants have been identified as causes for erythrocytosis in genes belonging to different pathways including oxygen sensing, erythropoiesis and oxygen transport. However, despite clinical investigation and screening for these mutations, the cause of disease cannot be found in a considerable number of patients, who are classified as having idiopathic erythrocytosis. In this study, we developed a targeted next-generation sequencing panel encompassing the exonic regions of 21 genes from relevant pathways (~79 Kb) and sequenced 125 patients with idiopathic erythrocytosis. The panel effectively screened 97% of coding regions of these genes, with an average coverage of 450×. It identified 51 different rare variants, all leading to alterations of protein sequence, with 57 out of 125 cases (45.6%) having at least one of these variants. Ten of these were known erythrocytosis-causing variants, which had been missed following existing diagnostic algorithms. Twenty-two were novel variants in erythrocytosis-associated genes (EGLN1, EPAS1, VHL, BPGM, JAK2, SH2B3) and in novel genes included in the panel (e.g. EPO, EGLN2, HIF3A, OS9), some with a high likelihood of functionality, for which future segregation, functional and replication studies will be useful to provide further evidence for causality. The rest were classified as polymorphisms. Overall, these results demonstrate the benefits of using a gene panel rather than existing methods in which focused genetic screening is performed depending on biochemical measurements: the gene panel improves diagnostic accuracy and provides the opportunity for discovery of novel variants.

PMID:
27651169
PMCID:
PMC5394871
DOI:
10.3324/haematol.2016.144063
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center