Table 2.
Clinical and Genetic Findings in Pediatric- and Adult-Onset aAA
| Patient Number |
Age Diagn. (yrs) |
Age WES (yrs) |
Sex | AA Duration (yrs) |
Severity | IST (Y/N) |
Time After IST (yrs) |
TL | TCR | Marrow Cellularity (%) |
WBC (103/µl)/ANC (cells/µl) |
Hgb (g/dL) |
Plt (103/µl) |
Disease Status at WES |
Karyotype | CN- LOH |
PNH Clone |
# Tier 1 & 2 Muts. |
Tier 1 Mutations | Tier 2 Mutations |
Other |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Pediatric-Onset aAA | |||||||||||||||||||||
| 362.01 | 1.5 | 2 | F | 1.2 | SAA | Y | 1.2 | N | n/a | 50–60 | 4.6/2521 | 9.6 | 146 | PR | Normal | None | None | 0 | None | None | |
| 387.01 | 2 | 3 | M | 0.5 | SAA | Y | 0.5 | N | Nl | 60–70 | 5.5/1282 | 7.9 | 52 | PR | Normal | None | None | 0 | None | None | |
| 439.01 | 3 | 4 | F | 0.8 | SAA | Y | 0.3 | N | Nl | 30–50 | 4.2/546 | 9.1 | 60 | PR | 47,XX, +der(15)c[20] |
None | None | 0 | None | None | |
| 281.01 | 3 | 4 | M | 0.7 | SAA | N | n/a | L | n/a | 80–90 | 5.7/1140 | 11.1 | 37 | PR | Normal | 6p | None | 1 | HLA-A (Y142X) | None | |
| 3.01 | 4 | 5 | M | 1.0 | SAA | Y | 1.0 | N | n/a | 70–80 | 5.5/3267 | 10.7 | 39 | PR | Normal | None | None | 0 | None | None | |
| 118.01 | 5 | 34 | F | 29.0 | SAA | Y | 18.0 | n/a | Clonal | n/a | 3.6/2500 | 8 | 39 | PR | Normal | None | Large | 5 |
HTR4 (K220N), TAF1C (D21N), GZMM (R37C), PIGA (V432fs) |
BFAR (3’UTR) |
PTPRD (syn) |
| 263.01 | 5 | 5 | F | 0.5 | SAA | Y | 0.5 | N | n/a | 30–40 | 3.0/990 | 9.6 | 15 | PR | Normal | None | Subclinical | 2 | None, PIGA# |
CYP4F24P (NCExonic) |
|
| 56.01 | 6 | 14 | M | 8 | VSA A | Y | 8 | L | n/a | 80–90 | 5.1/1647 | 10.9 | 35 | Rel. | Normal | 6p | None | 0 | None | None |
LCT (syn) |
| 54.01 | 10 | 21 | M | 11.0 | SAA | Y | 7.0 | L | Nl | 15 | 2.7/713 | 12.2 | 100 | PR | Normal | 6p | None | 1 | HLA-B (Leu294fs) | None |
LYPD8 (upstr) |
| 45.01 | 14 | 20 | M | 6.0 | SAA | Y | 6.0 | L | Nl | 10–70 | 3.7/1628 | 15.5 | 114 | PR | Normal | None | None | 0 | None | None | |
| 58.01 | 14 | 25 | F | 11.0 | SAA | Y | 10.0 | N | n/a | 50–60 | 4.0/1750 | 9.9 | 246 | CR | Normal | None | Moderate | 4 |
CDC14A(V166M), ERCC6L(R372X), PIGA (ex 2 splice) |
CYCS (3’UTR) | |
| 376.01 | 15 | 15 | F | 0.5 | SAA | Y | 0.5 | N | Nl | 60–70 | 3.6/1418 | 11.5 | 115 | PR | Normal | None | None | 0 | None | None | |
| 312.01 | 15 | 16 | M | 1.0 | SAA | Y* | 1.0 | N | Clonal | 50–60 | 5.1/3254 | 15.7 | 151 | Rel. | Normal | 15q | Moderate | 2 | PIGA# |
MOSPD1 (3’UTR) |
|
| 252.01 | 16 | 19 | F | 2.0 | SAA | Y | 2.0 | n/a | n/a | 80–90 | 3.3/1752 | 10.3 | 196 | CR | Normal | None | Large | 4 |
BCOR (V594I), PIGA (A313fs) |
MSRA (3’UTR), EPG5 (3’UTR) |
|
| 145.01 | 17 | 18 | F | 0.6 | VSA A | Y | 0.3 | N | Indetr. | 30–40 | 4.5/1080 | 9.7 | 14 | NR | Normal | None | Subclinical | 3 |
ZSCAN5B (Q322X), PIGA (F259fs) |
IL22RA2 (3’UTR) | |
| 020.01 | 17 | 26 | F | 9.0 | SAA | Y | 6.0 | L | Nl | 40 | 4.8/1890 | 11.2 | 41 | Rel. | Normal | 5q | Moderate | 6 |
CAMK2G (T306M), BPTF (D312H), WDR18 (A156T), PIGA# |
PDE10A (3’UTR), SLC2A13 (3’UTR) |
|
| 385.01 | 18 | 18 | M | 0.1 | VSA A | N | 0.0 | N | Nl | 0–50 | 3.4/942 | 10.9 | 24 | Diagn. | Normal | None | n/a | 4 |
EMX2 (A172V), DSG1 (M208V), PIGA (K88N) |
LARP (3’UTR) |
OR10A
7 (syn) |
| 434.01 | 19 | 19 | M | 0.3 | SAA | Y | 0.3 | N | Nl | 80 | 3.8/2481 | 12.8 | 162 | CR | Normal | None | None | 0 | None | None |
CHPF2 (upstr) |
| Adult-Onset aAA | |||||||||||||||||||||
| 364.01 | 33 | 36 | F | 3.0 | SAA | Y | 3.0 | N | Nl | 60 | 7/3730 | 8.7 | 62 | Refr. | Normal | None | None | 11 |
SLC22A6 (R336C), STAT5B (N642H), WFDC12 (G27C), DNAJC24 (ex4 splice) |
OSBPL11 (3’UTR), SENP6(3’UTR), MET(3’UTR), NFIB(3’UTR), ZNF747(3’UTR ), BLCAP(3’UTR), CLCN5 (3’UTR) |
|
| 76.01 | 38 | 44 | F | 6.0 | NSA A | N | n/a | N | Nl | 75 | 3.2/2260 | 8.1 | 124 | NSAA | Normal | None | Large | 9 |
CACNB3 (T347M), SLC12A5(M1073R), HHIP (R434G), ERCC6L (P947T), PIGA (I61fs) |
MUL1 (3’UTR), HSPB2 (3’UTR), SCN2B (3’UTR), RBL1 (3’UTR) |
|
| 356.01 | 53 | 53 | F | 0.3 | VSA A | Y | 0.3 | N | Nl | 35 | 4.1/2390 | 10.2 | 190 | PR | Normal | None | None | 8 |
SYNPO2(Q709K), IL20RA(Q473K), FOS(G97R), NINL(R667C), SEPT3(R165H), ASXL1(C687fs) |
LMTK2 (5’UTR), ATP2B3 (3’UTR) |
|
| 390.01 | 61 | 61 | F | 0.4 | VSA A | Y | 0.3 | N | Nl | 25 | 3.2/1920 | 8.3 | 32 | PR | 46,XX,del(13) (q12q14)[2]/ 46,XX[18] |
6 WC | Subclinical | 1 | PIGA(F438del.L439del) | None | |
SAA, severe aAA; VSAA, very severe aAA; NSAA, non-severe aAA. TL, telomere lengths (N: ≥10th percentile of normal, L: <10th percentile of normal). Marrow cellularity, bone marrow cellularity at the time of WES, performed at the corresponding disease duration (AA Duration), time from immunosuppression (Time After IST), and Disease Status (CR, complete response; PR, partial response; Rel., relapse, Refr., refractory aAA, Diagn., diagnosis). TCR, T-cell receptor rearrangement (Nl: polyclonal; Clonal; Inder.: indeterminate). PNH Clone (None (<1%), Subclinical (1–10%), Moderate (10–50%), Large (>50%)).
: In agreement with published studies of PIGA gene sequencing in PNH [1, 2], three patients had flow-cytometric evidence of PNH for which we were unable to identify a mutation by WES or bi-directional Sanger sequencing of the PIGA exons and their immediately flanking regions. These were likely caused by multiple independent mutations in PIGA below the level of detection of WES and Sanger sequencing [3].