Table 1.
Genes involved in predisposition to myelodysplastic syndrome/acute myeloid leukemia and important clinical features
| Syndrome | Gene(s) | Inheritance Mutation Types | Age of MDS/AML Onset (range, y) | Hematologic Features | Extrahematopoietic Features | Other Cancers | Implications for Management | References |
|---|---|---|---|---|---|---|---|---|
| Myeloid Neoplasms with Germline Predisposition Without Preexisting Disorder or Organ Dysfunction | ||||||||
| Familial AML with CEBPA mutations | CEBPA | AD Missense, FS |
Adult>Ped (range 1–62) | AML | — | — | Chemosensitive Risk of second primary AML |
47,48,81–86 |
| Familial MDS/AML with mutated DDX41 | DDX41 | AD Missense, FS, NS, CNV |
Older adult (range 40–89) | MDS, AML, CML Lymphoma |
Granulomatous and autoimmune disorders in a few families | — | — | 70,87–91 |
| Myeloid neoplasms with germline predisposition and preexisting platelet disorders | ||||||||
| ANKRD26-related thrombocytopenia | ANKRD26 | AD UTR variants; coding NS, missensea |
Adult (range 26–70) | MDS, AML, CML CMML, CLL Thrombocytopenia |
— | — | Mild bleeding tendency | 92–98 |
| ETV6-related thrombocytopenia | ETV6 | AD Missense, FS, NS |
Ped-Adult (range 8–82) | B-ALL, MDS, AML, CMML, DLBCL Variable thrombocytopenia |
Not shared across pedigrees (developmental delay, dysmorphisms, autoimmunities) | Colon, breast, meningioma | Mild to moderate bleeding tendency | 99–106 |
| Familial platelet disorder with propensity to AML | RUNX1 | AD Missense, FS, NS, CNV, rearrangements |
Adult>Ped (range 5–72) | MDS, AML, T-ALL, hairy cell leukemia, CMML Mild to moderate thrombocytopenia |
Case report of co-occurring eczema | — | — | 50,112–120 |
| Myeloid neoplasms with germline predisposition and other organ dysfunction | ||||||||
| Germline SAMD9/SAMD9L |
SAMD9 SAMD9L |
AD Missense |
Ped, rare adult (range 1–56) | AA, MDS, AML, CMMLa Increased prevalence of monosomy 7 |
MIRAGE syndrome (SAMD9) Ataxia-Pancytopenia (SAMD9L) |
— | — | 7,37,38,121–124 |
| Familial MDS/AML with GATA2 mutation | GATA2 | AD Missense, NS, FS, splicing, regulatory, CNV |
AYA (range 3–78) | AA, MDS, AML, CMML Increased prevalence of monosomy 7 |
Infection Lymphedema Pulmonary alveolar proteinosis Hearing loss |
— | — | 8,19,44,65,107–111 |
| Diamond-Blackfan anemia |
GATA1 RPL5 RPL11 RPL15 RPL23 RPL26 RPL27 RPL31 RPL35a RPL36 RPS7 RPS10 RPS15 RPS17 RPS19 RPS24 RPS26 RPS27 RPS27A RPS28 RPS29 TSR2 |
AD, X linked (GATA1, TSR2) Missense, FS, NS, splicing, CNV, 3′ UTR |
Adult>Ped (range 2–57) | Red cell aplasia, MDS, AML | Growth retardation, congenital malformations | Osteosarcoma, colon, possibly others | — | 69,125–128 |
| Fanconi anemia |
FANCA FANCB FANCC FANCD1/BRCA2 FANCD2 FANCE FANCF FANCG FANCI FANCJ/BRIP1 FANCL FANCM FANCN/PALB2 FANCO/RAD51C FANCP/SLX4 FANCQ/ERCC4 FANCR/RAD51 FANCS/BRCA1 FANCT/UBE2T FANCU/XRCC2 FANCV |
AR AD (FANCR) X linked (FANCB) Missense, FS, NS, splicing, CNV |
AYA (range 1–57) | AA, MDS, AML ALL with FANCD1 |
Short stature, developmental delay, skeletal and renal abnormalities | SCC of head, neck and anogenital region | Require attenuated therapy, radiosensitive | 61,69,129–132 |
| Short telomere syndromes |
ACD/TPP1 CTC1 DKC1 NAF1 NHP2 NOP10 PARN POT1 RTEL1 TR TERT TINF2 WRAP53/TCAB1 ZCCHC8 |
AD, AR, X linked Missense, FS, NS, splicing, CNV TR: SNV, INDELs |
Adult>Ped (range 2–77) | AA, MDS, AML | Mucocutaneous features, pulmonary fibrosis, liver disease, immunodeficiency, enteropathy, severe congenital anomalies in some | SCC of head, neck and anogenital region | Attenuated regimen, radiosensitive | 69,79,80,133–144 |
| Shwachman-Diamond |
SBDS DNAJC21 EFL1 |
AR Missense, FS, NS, splicing, CNV |
AYA (range 2–53) | Neutropenia, MDS, AML | Exocrine pancreatic insufficiency, neurodevelopmental and skeletal abnormalities | — | — | 2,38,69,145–147 |
| Traditional Hereditary Cancer Predisposition Syndromes | ||||||||
| Li-Fraumeni |
TP53 CHEK2 |
AD Missense, FS, NS, splicing, intronic, CNV |
Ped + adult (range 4–50) | ALL, MDS, AML, CML, lymphoma | — | Breast, sarcoma, CNS, adreno cortical carcinoma | — | 6,148–152 |
Abbreviations: AA, aplastic anemia; AD, autosomal dominant; ALL, acute lymphoblastic leukemia; AR, autosomal recessive; AYA, adolescent and young adult population; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; CNV, copy number variant; DLBCL, diffuse large B-cell lymphoma; FS, frameshift; MIRAGE, myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy; NS, nonsense; Ped, pediatric-onset disease; SCC, squamous cell carcinoma.
a
Finding reported in a single family or case report.