TABLE 1.
Genetic mutations and associated phenotype in HS due to SPTA1 mutations.
| Phenotype | Patient | Allele 1 | Allele 2 | Age at time of report and comments | Ektacytometry | α-spectrin in RBC ghosts (% of control) |
| GROUP I (patients 1–4) Severe, recessive HS (transfusion-dependent, responding to splenectomy) | 1 | c.4339-99C > T | c.4295del (p.L1432*) | 11 year-old, chronic transfusion requirement with partial response to partial splenectomy, resolved after total splenectomy |  |
54% |
| 2 | c.4339-99C > T | c.5102A > T (p.L1701*) | 7 year-old, chronic transfusion requirement, improved with partial splenectomy |  |
64% | |
| 3 | c.4339-99C > T | c.3267A > T (p.Y1089*) | 11 year-old, not splenectomized due to family preference, continues to require frequent transfusions | Not evaluable in a transfused sample | ||
| 4 | Mutation not identified | Gross deletion of SPTA1 | 3.5 year-old, RT-PCR demonstrated significantly decreased α-spectrin expression; hemoglobin has normalized after recent splenectomy | Not evaluable in a transfused sample | ||
| GROUP II (patients 5–8) Severe to moderately severe, recessive HS | 5 | c.4339-99C > T | c.1120C > T (p.R374*) | 4 year-old, chronic transfusion requirement for first three years with improved pattern since. | Sample not provided after age 3, when transfusion-independent | |
| 6 | c.4339-99C > T | c.1351-1G > T | 7 year-old, occasional transfusion requirement, resolved after splenectomy at 5 years of age |  |
59% | |
| 7 | c.4339-99C>T | c.2671C > T (p.R891*) | 4 year-old, has not been transfused so far, Hgb 7.1-8.9 g/dL, ARC 420-572 x 103/μl. |  |
61% | |
| 8 | c.4339-99C > T | c.3257delT | 8 year-old, transfused once as neonate, Hgb 10.6–11.8 g/dL, ARC 354–535 × 103/μl; now Hgb 15–16 g/dL with normal ARC after splenectomy at 6 years of age (splenectomy performed because of chronic abdominal pain due to co-morbidities) |  |
Not performed. | |
| GROUP III (patients 9-11) Life-threatening anemia in utero leading tofatal hydrops fetalis if untreated (transfusion-dependent, not responding to splenectomy) | 9 | c.4206delG (fs) | c.4180delT (fs) in haplotype with c.6631C > T (p.R2211C) | Died at birth. Post-mortem diagnosis from parental studies and DNA extracted from liver tissue saved in paraffin block | N/A | |
| 10 | c.6788+11C > T | c.6788+11C > T | 11 year-old, born prematurely at EGA of 33 weeks with hydrops fetalis, remained transfusion-dependent even after splenectomy; now doing well after matched sibling transplant | Not evaluable in a transfused sample (required chronic transfusions up until bone marrow transplant) | 26% (performed in CD71+ cells) | |
| 11 | c.6154del (p.Ala2052fs) | c.6154del (p.Ala2052fs) | 2 year-old, severe in-utero anemia requiring five in-utero transfusions. Born with severe neonatal hyperbilirubinemia requiring exchange transfusion. Remains transfusion-dependent | Not evaluable in a transfused sample | ||
Of note, all the SPTA1 variants reported here except c.4339-99C > T (αLEPRA) and c.2671C > T; p.R891* (Bogardus et al., 2014) have not been previously described.