Molecular study of congenital erythrocytosis in 70 unrelated patients revealed a potential causal mutation in less than half of the cases (Where is/are the missing gene(s)?)

Abstract

IntroductionCongenital Erythrocytosis can be classified as primary, when the defect is intrinsic to the RBC progenitors and independent of the serum erythropoietin (Epo) concentration, or secondary, when the erythrocytosis is the result of an up-regulation of Epo production. Primary erythrocytosis is associated with mutations in the EPOR gene, secondary congenital erythrocytosis can de due to mutations that stabilize the hemoglobin in the oxygenated form or to mutations in the genes that control the transcriptional activation of the EPO gene -VHL, EGLN1, EPAS1. Material and MethodsWith the main objective of describing the etiology and molecular basis of congenital erythrocytosis we have studied 70 consecutive unrelated patients presenting with idiopathic erythrocytosis from our hematology clinic or referred from other centers. According to a study algorithm we have sequenced all the genes described as associated with congenital erythrocytosis. Results and DiscussionErythrocytosis molecular etiology was identify in 25 (36%) of the 70 subjects. High-affinity Hb variants were the most common cause, present in 20% of the cases. New mutations were identified in the JAK2, EPOR, VHL and EGLN1 genes. Conclusions High affinity hemoglobin variants are a very rare cause of secondary congenital erythrocytosis, but it seems likely that their incidence may be underestimated. Our experience shows that in erythrocytosis with a dominant inheritance and normal or inappropriate high Epo levels, the HBB and HBA genes should be the first to be studied. In spite of the seven genes known to be involved in congenital erythrocytosis, the majority of the cases have unknown etiology.

Erythrocytosis associated with a novel missense mutation in the BPGM gene

“…Recently, Bento et al sequenced 70 cases of idiopathic erythrocytosis, including sequencing of BPGM in cases with high Epo and no BPGM mutations were identified. 15 Interestingly, the same amino acid residue (i.e. arginine at codon 90) is affected, as in previous cases of erythrocytosis.…”

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

“…If the patient's erythropoietin level is high or normal, the P50 (partial pressure of oxygen at which 50% of hemoglobin is saturated with oxygen) is calculated and if low, hemoglobin electrophoresis is performed and/or variants in oxygen-delivery pathways (globin genes, BPGM) are screened for; if P50 is normal or not available, variants in the oxygen-sensing HIF pathway (VHL, EPAS1, EGLN1) are screened for. 2,29,30 Using our gene panel we were able to provide definitive genetic diagnoses in nine patients whose mutations had been previously missed. For example, a variant in EPAS1, p.G537R -a well-described gain-of-function mutation found in erythrocytosis patients 31,32 -was detected.…”

A Japanese Family with Congenital Erythrocytosis Caused by Haemoglobin Bethesda

“…According to these findings, we strongly suspected the presence of a Hb variant with a high oxygen affinity or 2,3-BPGM deficiency (1)(2)(3)(4)(5).…”

“…The presence of a high oxygen affinity Hb variant or 2,3-biphosphoglycerate mutase (BPGM) deficiency impairs oxygen release to the tissues. The oxygen dissociation curve (ODC) is shifted to the left and leads to inappropriately raised serum EPO levels with high Hb values (1)(2)(3)(4). In this report, we describe a Japanese family who carry the Hb Bethesda variant, a haemoglobinopathy with a high oxygen affinity, and demonstrate the importance of determining the P50 value in the ODC for an accurate diagnosis.…”

“…Acquired secondary erythrocytosis is the most common form and can be caused by a high-altitude habitat, heavy smoking, or various disorders (e.g., chronic obstructive pulmonary disease, congenital heart disease, and EPO-producing tumour) (1)(2)(3)(4). When these causes are excluded, a genetic cause involving haemoglobin (Hb) variants or the proteins of the oxygen-sensing pathway should be suspected, although these causes are rare (1)(2)(3)(4). The presence of a high oxygen affinity Hb variant or 2,3-biphosphoglycerate mutase (BPGM) deficiency impairs oxygen release to the tissues.…”