Table 2.
Genetic and clinical characteristics of individuals with monoallelic PSMB10 variants
| Individual 1 | Individual 2 | Individual 3 | Individual 4 | Individual 5 | Individual 6 | |
|---|---|---|---|---|---|---|
| Genetics | ||||||
| Ancestry | European | Jewish-Sepharadi | European | European | European | European |
| Variant | c.601G>A (p.Gly201Arg) | c.601G>A (p.Gly201Arg) | c.601G>C (p.Gly201Arg) | c.601G>A (p.Gly201Arg) | c.166G>C (p.Asp56His) | c.601G>A (p.Gly201Arg) |
| Allele frequencya | 0 | 0 | 0 | 0 | 0 | 0 |
| CADD-Phred score | 35 | 35 | 34 | 35 | 28 | 35 |
| Clinical presentation | ||||||
| Age at investigation (weeks) | 8 | 2 | 6 | 13 | 4 | 0c |
| Sex | M | M | M | F | M | M |
| Failure to thrive | + | + | + | + | + | – |
| Diarrhea | + | +++ | + | + | +++ | + |
| Skin rash | +++ | + | +++ | +++ | ++ | + |
| Age at onset rash (weeks) | <1 | 2 | 3 | 1 | 8 | <1 |
| Recurrent infections | + | + | + | + | + | – |
| Systemic inflammation | – | + | – | – | – | – |
| Hepatomegaly | – | – | + | + | – | – |
| Lymphadenopathy | + | – | – | – | + | – |
| Alopecia | + | + | + | + | N/A | – |
| Dysmorphology | + | + | – | – | – | – |
| Laboratory investigationb | ||||||
| Eosinophils (/μL) (40–800) | 896 | 2,930 | 1,700 | 1,700 | 720 | 1,000 |
| IgG (g/L) (3.7–12.6) | 1.35 | 0.974 | 2.6 | 2.76 | 5.1 | 2.4 |
| IgA (g/L) (0.02–0.15) | <0.07 | <0.01 | <0.07 | 0.23 | 0.41 | <0.04 |
| IgM (g/L) (0.05–0.29) | <0.07 | <0.02 | 0.09 | 0.12 | 0.98 | <0.04 |
| CD3 (/μL) (1,700–3,600) | 1,300 | 1,552 | 595 | 1,239 | 188 | 309 |
| CD4 (/μL) (1,700–2,800) | 1,100 | 730 | 551 | 1,143 | 137 | 272 |
| CD8 (/μL) (800–1,200) | 40 | 820 | 72 | 83 | 26 | 60 |
| CD4:CD8 ratio | 27.5 | 0.89 | 7.7 | 13.8 | 5.3 | 4.5 |
| CD19 (/μL) (500–1500) (%) | 40 | 430 (cells/mm3) | 0 | <1 | 19 | 34 |
| CD3/CD56 (/μL) (300–700) | 70 | 1,826 | 46 | 414 | 22 | 368 |
| CD45RA (%CD3) | 8.6 | N/Ac | 1 | 0 | 8 | 0 |
| CD45RO (%CD3) | 95 | N/Ac | 91 | N/A | N/A | 4 |
| TCR αβ (%CD3) | 98 | N/A | 97 | 99 | 74 | 96 |
| TCR γδ (%CD3) | 2 | N/A | 3 | 1 | 26 | 4 |
| Mitogen response (PHA) | decreased | decreased | decreased | decreased | decreased | decreased |
| Therapy–Hematopoietic stem cell transplantation (HSCT) | ||||||
| Age at transplant (weeks) | 12 | 130 | 11 | 16 | 12 | 9 |
| Donor information | HLA identical sibling | URD | URD cord | maternal haplo | 9/10 mM cord blood | paternal haplo |
| Serotherapy | ATG | ATG | alemtuzumab | ATG | none | ATG + Rituximab |
| Chemotherapy | Cyclo | Cyclo + MMF | Flu + Mel | Bu + Cyclo | Treo + Flu | Treo + Flu |
| Outcome and follow up | alive, age 18 years | died, age 2 years | died, age 16 years | died, age 11 weeks | died, age 4 years | alive, age 0–1 year |
| 100% donor skin/gut GVHD marked infection- and drug-induced hyperresponsivity of the skin |
100% donor fatal transplant-associated TMA |
100% donor skin GVHD severe VOD long-term enteropathy liver cirrhosis ESRD (hemodialysis) |
pneumonitis with capillary leak peri-engraftment GVHD skin and gut recurrence of VZV with fatal encephalopathy |
100% donor skin GVHD (late) marked mucositis and skin toxicity adenoviraemia long-term enteropathy with norovirus infections |
100% donor no GVHD episode of acute encephalopathy currently <3 months post-HSCT |
|
ATG, antithymocyte globulin; Bu, busulfan; CADD, combined annotation dependent depletion; Cyclo, cyclophosphamide; ESRD, end-stage renal disease; Flu, fludarabine; GVHD, graft-versus-host disease; Mel, melphalan; MMF, mycophenolate mofetil; TREC, T cell receptor excision circles; Treo, treosulfan; URD, unrelated donor; VOD, veno-occlusive disease; VZV, varicella zoster virus.
a
Allele frequency in GnomAD, dbSNP or ExAC databases.
b
Parameters are presented with units and normal reference ranges if applicable.
c
For this individual, TREC copies were available with significantly reduced levels.