Common adaptive somatic genetic rescue mechanisms and maladaptive responses in inherited bone marrow failure and MDS predisposition syndromes and their association with risk of progression to MDS/AML
| . | Lower risk (adaptive rescue) . | Higher risk (maladaptive response) . |
|---|---|---|
| SAMD9/9L syndromes | Second-site loss-of-function mutation (cis) UPD 7q | -7 / del7q |
| Shwachman-Diamond syndrome | EIF6 inactivating mutation Deletion 20q Isochromosome 7q | TP53 mutation |
| GATA2 deficiency | Direct reversion* | -7 / del7q / der(1;7) |
| Fanconi anemia | Direct reversion | |
| RUNX1-FPDMM | UPD 21q** | Somatic 2nd-hit RUNX1 mutation (trans) |
| Short telomere syndromes | Direct reversion TERT promoter mutation POT1 loss-of-function mutation RNA exosome mutation | -7 / del7q / der(1;7) TP53 mutation |
| DDX41 | — | Somatic 2nd-hit DDX41 mutation (trans) |
| . | Lower risk (adaptive rescue) . | Higher risk (maladaptive response) . |
|---|---|---|
| SAMD9/9L syndromes | Second-site loss-of-function mutation (cis) UPD 7q | -7 / del7q |
| Shwachman-Diamond syndrome | EIF6 inactivating mutation Deletion 20q Isochromosome 7q | TP53 mutation |
| GATA2 deficiency | Direct reversion* | -7 / del7q / der(1;7) |
| Fanconi anemia | Direct reversion | |
| RUNX1-FPDMM | UPD 21q** | Somatic 2nd-hit RUNX1 mutation (trans) |
| Short telomere syndromes | Direct reversion TERT promoter mutation POT1 loss-of-function mutation RNA exosome mutation | -7 / del7q / der(1;7) TP53 mutation |
| DDX41 | — | Somatic 2nd-hit DDX41 mutation (trans) |
Direct reversion in Fanconi anemia and the short telomere syndromes encompasses multiple mechanisms, including uniparental isodisomy of the wild-type allele, somatic second-site loss-of-function mutation, and back mutation, that individually are seen more rarely.
Single case report by Catto et al found somatic reversion of a germline nonsense mutation in GATA2 to a synonymous mutation in an asymptomatic 61-year-old adult.54
Single case report by Glembotsky et al of somatic reversion via uniparental isodisomy of chromosome 21 in an individual with germline RUNX1 mutation and gradual improvement platelet number and function.75
RUNX1-FPDMM, RUNX1 familial platelet disorder with associated myeloid malignancies; UPD, uniparental isodisomy.