TABLE 2.
Reported variants of the human BPGM gene associated with erythrocytosis
| Reference | BPGM variant | Allele frequency a | No. of subjects (Inheritance) | Haematological and functional phenotype | Clinical phenotype | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Hb, g/l | Hct, % | RBC, ×1012/l | EPO, u/l | BPGM activity, u/g Hb | 2,3‐BPG, μmol/g Hb | P50, mmHg | Clinical data | ||||
| Normal range b | NA | NA | NA |
M:139–172 F:119–155 |
M:41–50 F:36–46 |
M:4.2–5.5 F:3.7–5.0 |
3–32 | NA b | NA b | 24.3 ± 1.4 | |
| Oliveira et al. (2018) 9 | c.127A > C p.(Lys43Gln) c | NA | 2 (Heterozygote) |
143–183 (normal: 120–160) |
NA | NA | NA | NA | NA | NA | Asymptomatic patients, relationship unknown |
| Oliveira et al. (2018) 9 | c.184C > T p.(Arg62Trp) | 3.98−6 | 1 (Heterozygote) |
200 (normal: 120–160) |
NA | NA |
21.6 (normal: 2.6–18.5) |
NA | NA |
31 (normal: 24–30) |
Patient with syncope, headaches, and fatigue responsive to phlebotomy and ASA therapy |
| Hoyer et al. (2004) 10 | c.185G > A p.(Arg62Gln) | 1.06−5 | 1 (Homozygote); | 192 | 58.9 | 6.22 |
8 (normal: 4–24) |
0.16 (~3% of normal) |
0.3 (~2% of normal) |
19 (normal: 25–30) |
Iranian Jewish (Meshadi), consanguine family: 28‐year‐old man with plethora |
| c.185G > A p.(Arg62Gln) | 3 (Heterozygote) | 134–164 | 40.5–46.1 | 4.56–5.72 | NA | 2.52–4.79 (50%–100% of normal) |
8.7–14.4 (50%–100% of normal) |
27–28 (normal: 25–30) |
The two asymptomatic parents and male sibling of the family mentioned above | ||
| Lazana et al. (2021) 11 | c.260 T > C p.(Leu87Pro) | NA | 1 (Homozygote, uniparental disomy); | 165–184 | 52–55 | NA | 9.7 | NA | NA |
18 (normal: 27–33) |
60‐year‐old female who became lethargic, breathless on exertion and experienced headaches during regular phlebotomy therapy |
| c.260 T > C p.(Leu87Pro) | 1 (Heterozygote) | NA | NA | NA | NA | NA | NA | NA | Her son with a normal haematological and clinical phenotype | ||
|
Rosa et al. (1978) 12 ; Galacteros et al. (1984) 13 ; Lemarchandel et al. (1992) 14 |
c.268C > T p.(Arg90Cys) and c.61delC p.(Arg21Valfs*28) |
7.97−6 NA |
4 (Compound heterozygote); |
168–190 | 52–60 |
5.0–5.9 |
NA | Undetectable | 0.3–0.4 (~3% of normal) | 17.3–22 | French family: 42‐year‐old man with headaches and ruddy (red) complexion who died of brain cancer, and three sisters with the same phenotype. Their parents died of vascular events aged 75 and 77 years |
| c.268C > T p.(Arg90Cys) | 7.97−6 | 3 (Heterozygote) | 143–180 | 43–56 | 4.9–5.6 | NA |
2.33–2.53 (40%–50% of normal) |
9.2–11.3 (~60% of normal) |
19.5–24 | Three offspring (one woman and two men) of the family mentioned above with intermediate phenotype | |
| Petousi et al. (2014) 3 ; | c.269G > A p.(Arg90His) | 1.06−5 | 2 (Heterozygote); |
155–193 (normal: M: 130–180; F: 115–155) |
58.6 d |
5.2–6.5 (normal: M: 4.5–6.5; F: 3.9–5.6) |
7.5–15.9 (normal: 2.5–10.5) |
3.27–3.62 (65%–85% of normal) |
11.3–14.5 (40%–80% of normal) |
23.9 e (normal 27–33) |
Three unrelated Caucasian families: − 27‐year‐old man with fatigue and his asymptomatic mother |
| This study | c.269G > A p.(Arg90His) | 2 (Heterozygote); | 163–182 |
51–59 |
6.0–6.7 |
46 b − 56 ( b normal: 4–20) |
4.0–4.5 (55%–70% of normal) |
11.8–14.7 (40%–50% of normal) |
18.9–19.1 | − 56‐year‐old and 60‐year‐old asymptomatic male siblings | |
| c.269G > A p.(Arg90His) | 1 (Heterozygote) | 193 | 57 | 6.3 | 2 |
3.8 (55% of normal) |
14.4 (50% of normal) | 18.5 | − 32‐year‐old man with headaches and tinnitus | ||
| Camps et al. (2016) 15 |
c.304C > A p.(Gln102Lys) |
NA | 1 (Heterozygote) |
186 (normal: 130–180) |
52.5 (normal: 45–52) |
NA | Normal | NA | NA | NA | A 52‐year‐old man with a medical history of myocardial infarction |
| Oliveira et al. (2018) 9 | c.344G > A p.(Trp115*) | NA | 1 (Homozygote) |
193 (normal: 120–160) |
NA | NA |
10 (normal: 2.6–18.5) |
NA | NA |
27 (normal: 24–30) |
Asymptomatic patient with thrombocytopenia |
| Oliveira et al. (2018) 9 | c.506G > A p.(Trp169*) | NA | 1 (Heterozygote) |
155 (normal: 120–160) |
NA | NA |
5.7–19.2 (normal: 2.6–18.5) |
NA | NA |
29 (normal: 24–30) |
Asymptomatic patient |
| Present study |
c.535C > T p.(Arg179Cys) |
3.98−5 | 2 (Heterozygote) | 168–200 | 49–57 | 5.5–6.5 | 7 |
5.5–5.7 (80%–90% of normal) |
21.7–25.6 (75%–90% of normal) | 20.0–20.1 | A 65‐year‐old woman with headaches with phlebotomy and ASA therapy, and her 39‐year‐old son with a medical history of retinal vein occlusion |
| Oliveira et al. (2018) 9 | c.‐409_‐398del12 c | NA | 1 (Heterozygote) | NA | NA | NA | NA | NA | NA | NA | Besides erythrocytosis: unknown |
| Oliveira et al. (2018) 9 | c.‐403C > T c | NA | 1 (Heterozygote) |
167 (normal: 120–160) |
NA | NA |
3.4 (normal: 2.6–18.5) |
NA | NA |
23 (normal: 24–30) |
Positive family history and symptoms, not otherwise specified, were reported |
| Oliveira et al. (2018) 9 | c.‐382‐35G > C c | NA | 3 (Heterozygote) |
185 (normal: 120–160) |
NA | NA |
13.4 (normal: 2.6–18.5) |
NA | NA |
19 (normal: 24–30) |
Positive family history, fatigue and splenomegaly were reported by at least one person with the variant |
Abbreviations: ASA, acetylsalicylic acid; 2,3‐BPG, 2,3‐bisphosphoglycerate; BPGM, bisphosphoglycerate mutase; EPO, erythropoietin; F, female; Hb, haemoglobin; Hct, haematocrit; M, male; NA, not available; P50, oxygen pressure at an oxygen saturation of 50% during deoxygenation; RBC, red blood cells.
Allele frequency data of the total population are based on the gnomAD version2.1.1.
Normal ranges based on our local laboratory reference range; if other normal ranges were mentioned in the referred paper, these were reported separately in the table. For BPGM activity and 2,3‐BPG levels, data were normalised to 100% for healthy control samples.
Classified as variants of unknown significance.
Hct only reported of the proband.
Calculated P50 value based on arterial blood gas analysis reported instead of a p50 value based on automatic measurement of the oxygen dissociation curve.