Clinical characteristics secondary to germline mutations affecting the TFs RUNX1, GATA2, and CEBPA
| . | RUNX1 . | GATA2 . | CEBPA . |
|---|---|---|---|
| HM | MDS, AML, T-ALL, T-NHL, CLL, HCL | MDS, AML, aCML, CMML | AML |
| Cytopenia | Thrombocytopenia | Monocytopenia, dendritic cell, B and NK lymphoid deficiency, chronic neutropenia | No preleukemic cytopenias |
| Other presentations | Easy bruising, epistaxis, eczema, petechiae, psoriasis | Lymphedema; pulmonary alveolar proteinosis; recurrent bacterial, fungal, and viral infections associated with immunodeficiencies; deafness; urogenital tract anomalies; behavioral problems | No preleukemic phenotype |
| Germline mutation types | Whole and partial gene deletions, intragenic deletions, truncating, missense (mainly in RUNT domain), splicing mutations | Whole and partial gene deletions, intronic deletions, truncating, missense and indels (zinc finger 2), intronic enhancer | N-terminal frameshift, C-terminal missense |
| Technology considerations for germline mutation detection | Coding SNVs and small indels: WGS, WES, NGS panels, Sanger, AFLP (CEBPA), MLPA. Larger CNVs: WGS, MLPA, SNP microarray. Noncoding variants: WGS, custom NGS panels, RNA sequencing (splicing alterations and expression) | ||
| Mutation-specific phenotype correlations | Dominant-negative mutations: earlier onset and increased penetrance of HM? | De novo LoF mutations common in pediatric MDS | N-terminal mutations: 90% penetrance of AML |
| T354M: mostly early-onset MDS/AML | C-terminal mutations: 50% penetrance of AML | ||
| R396Q and R398W: mostly immune defects and MDS | |||
| Common second hits (Figure 1D-F) | Somatic RUNX1 [including UPD 21, +21(q)], PHF6, BCOR, NOTCH1, EZH2 | −7, +8, ASXL1, NRAS, WT1, STAG2, KRAS, SETBP1 | Somatic CEBPA, WT1, GATA2, KIT, TET2, EZH2 |
| Mutation spectrum | Overlap between germline and somatic mutations | Distinct mutational pattern for germline (truncating, ZF2 missense and indels, intronic enhancer) and somatic (mostly ZF1 missense and some ZF2 missense) mutations | Overlap between germline and somatic mutations (N- and C-terminal regions; however poor sequence coverage in past may have masked some mutations) |
| Mode of germline mutation | Inherited predominant, de novo infrequent (except large chromosome deletions) | Inherited and de novo mutations frequently reported | Wholly inherited, with no published reports of de novo mutation |
| NGS Gene coverage gnomAD | Complete (canonical transcript) | Complete | Poor (<20× for ∼70% of coding region) |
| Age of onset, median, y | 29 | 19 | 23 |
| Age of onset, range (y), % | |||
| <10 | 17.1 | 13.4 | 25.9 |
| 11-20 | 13.0 | 39.7 | 22.4 |
| 21-30 | 14.6 | 21.5 | 17.3 |
| 31-40 | 11.4 | 10.6 | 15.5 |
| 41-50 | 19.5 | 9.0 | 8.6 |
| 51-60 | 16.3 | 3.9 | 8.6 |
| >61 | 8.1 | 1.9 | 1.7 |
| Presymptomatic monitoring and treatment | Patient monitoring depends on local guidelines and expert opinion | ||
| Chemotherapy (GATA2, RUNX1, CEBPA), followed by HSCT (GATA2, RUNX1). Evidence-based conclusions on best treatments and monitoring options not available because of small cohort sizes and lack of data aggregation for rare disorders. | |||
| Prognosis | Not well defined for germline. Poor for sporadic/somatic RUNX1 mutated. | Poor for leukemic patients. HSCT for immune deficiency and leukemia prevents progression with favorable outcome. | Generally favorable long-term outcomes with chemotherapy alone |
| . | RUNX1 . | GATA2 . | CEBPA . |
|---|---|---|---|
| HM | MDS, AML, T-ALL, T-NHL, CLL, HCL | MDS, AML, aCML, CMML | AML |
| Cytopenia | Thrombocytopenia | Monocytopenia, dendritic cell, B and NK lymphoid deficiency, chronic neutropenia | No preleukemic cytopenias |
| Other presentations | Easy bruising, epistaxis, eczema, petechiae, psoriasis | Lymphedema; pulmonary alveolar proteinosis; recurrent bacterial, fungal, and viral infections associated with immunodeficiencies; deafness; urogenital tract anomalies; behavioral problems | No preleukemic phenotype |
| Germline mutation types | Whole and partial gene deletions, intragenic deletions, truncating, missense (mainly in RUNT domain), splicing mutations | Whole and partial gene deletions, intronic deletions, truncating, missense and indels (zinc finger 2), intronic enhancer | N-terminal frameshift, C-terminal missense |
| Technology considerations for germline mutation detection | Coding SNVs and small indels: WGS, WES, NGS panels, Sanger, AFLP (CEBPA), MLPA. Larger CNVs: WGS, MLPA, SNP microarray. Noncoding variants: WGS, custom NGS panels, RNA sequencing (splicing alterations and expression) | ||
| Mutation-specific phenotype correlations | Dominant-negative mutations: earlier onset and increased penetrance of HM? | De novo LoF mutations common in pediatric MDS | N-terminal mutations: 90% penetrance of AML |
| T354M: mostly early-onset MDS/AML | C-terminal mutations: 50% penetrance of AML | ||
| R396Q and R398W: mostly immune defects and MDS | |||
| Common second hits (Figure 1D-F) | Somatic RUNX1 [including UPD 21, +21(q)], PHF6, BCOR, NOTCH1, EZH2 | −7, +8, ASXL1, NRAS, WT1, STAG2, KRAS, SETBP1 | Somatic CEBPA, WT1, GATA2, KIT, TET2, EZH2 |
| Mutation spectrum | Overlap between germline and somatic mutations | Distinct mutational pattern for germline (truncating, ZF2 missense and indels, intronic enhancer) and somatic (mostly ZF1 missense and some ZF2 missense) mutations | Overlap between germline and somatic mutations (N- and C-terminal regions; however poor sequence coverage in past may have masked some mutations) |
| Mode of germline mutation | Inherited predominant, de novo infrequent (except large chromosome deletions) | Inherited and de novo mutations frequently reported | Wholly inherited, with no published reports of de novo mutation |
| NGS Gene coverage gnomAD | Complete (canonical transcript) | Complete | Poor (<20× for ∼70% of coding region) |
| Age of onset, median, y | 29 | 19 | 23 |
| Age of onset, range (y), % | |||
| <10 | 17.1 | 13.4 | 25.9 |
| 11-20 | 13.0 | 39.7 | 22.4 |
| 21-30 | 14.6 | 21.5 | 17.3 |
| 31-40 | 11.4 | 10.6 | 15.5 |
| 41-50 | 19.5 | 9.0 | 8.6 |
| 51-60 | 16.3 | 3.9 | 8.6 |
| >61 | 8.1 | 1.9 | 1.7 |
| Presymptomatic monitoring and treatment | Patient monitoring depends on local guidelines and expert opinion | ||
| Chemotherapy (GATA2, RUNX1, CEBPA), followed by HSCT (GATA2, RUNX1). Evidence-based conclusions on best treatments and monitoring options not available because of small cohort sizes and lack of data aggregation for rare disorders. | |||
| Prognosis | Not well defined for germline. Poor for sporadic/somatic RUNX1 mutated. | Poor for leukemic patients. HSCT for immune deficiency and leukemia prevents progression with favorable outcome. | Generally favorable long-term outcomes with chemotherapy alone |
aCML, atypical chronic myeloid leukemia; AFLP, amplified fragment length polymorphism; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CMML, chronic myelomonocytic leukemia; CNV, copy number variant; HCL, hairy cell leukemia; HSCT, hematopoietic stem cell transplantation; LoF, loss of function; MDS, myelodysplastic syndrome; MLPA, multiplex ligation-dependent probe amplification; NGS, next-generation sequencing; NK, natural killer; SNP, single nucleotide polymorphism; SNV, single nucleotide variant; T-ALL, T-cell acute lymphoblastic leukemia; T-NHL, T-cell non-Hodgkin lymphoma; WES, whole-exome sequencing; WGS, whole-genome sequencing; ZF, zinc finger.