Certain germline gene mutations lead to an increased risk of myeloid neoplasms, in addition to congenital abnormalities affecting various organs and systems. The age of presentation for myeloid neoplasms varies among different genes and can exhibit heterogeneity even within the same family. While certain neoplasms, such as JMML in RASopathies, often occur in infants and toddlers, the median age of onset for AML in individuals with Fanconi Anemia is typically around 7-8 years.¹ On the other hand, most other myeloid neoplasms associated with germline predisposition manifest between the ages of 20 and 40.² The penetrance rates for myeloid neoplasms associated with germline predisposition also vary depending on the genes involved. The following are the estimated penetrance rates for hematopoietic malignancies: CEBPA mutations: almost 100% ³ GATA2 mutations: 70-75% ⁴ RUNX1 mutations: 35-40% ⁵ Severe Congenital Neutropenia (SCN): 10-20% ⁶, ⁷ Shwachman-Diamond syndrome (SDS): 10-30% ⁸ Fanconi anemia (FA): 10-30% ⁹, ¹⁰ DKC1 mutations (Dyskeratosis Congenita): 3-33% ¹¹ SAMD9L mutations: 70% ¹² ANKRD26 mutations: 8% ⁵ The table below lists germline mutations that lead to dominantly inherited myeloid neoplasms. Please note that it does not include other germline mutations associated with solid tumors and hematopoietic malignancies such as Li-Fraumeni syndrome.

Pediatric Myeloid neoplasms associated with germline predisposition	Genetic marker(s)	Table
CEBPA-associated familial AML	The dominant driver gene of CEBPA-associated familial AML is the CEBPA mutation. The inherited mutation in CEBPA is often located in the N-terminal region, while the somatic mutation is typically found in the C-terminal region, specifically within the b-ZIP domain of CEBPA. Karyotype is typically normal.13
Familial platelet disorder with associated myeloid malignancy	The dominant driver gene is the RUNX1 mutation. Additional frequently mutated genes include FLT3, BCOR, GATA2.14 Additional chromosome aberrations include monosomy 7.
GATA2-deficiency	The dominant driver gene is the GATA2 mutation. Additional frequently mutated genes include RUNX1, SETBP1, IKZF1, CRLF2.15 Additional chromosome aberrations include monosomy 7 or trisomy 8.
Severe congenital neutropenia	Mutations of the ELANE, HAX1, SRP54 are common drivers in pediatric severe congenital neutropenia.16-18 Common chromosomal aberrations include monosomy 7.
Shwachman-Diamond syndrome	Mutations of the SBDS, EFL1, DNAJC21, SRP54 are common drivers in pediatric Shwachman-Diamond syndrome.19
Fanconi anemia	Mutations of the FANCA, FANCC, FANCG (>22 genes) are common drivers in pediatric Fanconi anemia. Mitomycin C-induced chromosomal breakage is a characteristic finding in this disease.20
Dyskeratosis congenita and other telomere biology disorders	Mutations of the DKC1, TINF2, TERC, TERT, NHP2, NOP10, NAF1, PARN, WRAP53, ACD, STN1, CTC1, RTEL1, TINF2, POT1 are common drivers in pediatric Dyskeratosis congenita and other telomere biology disorders. 21
Rasopathies	Mutations of the NF1, CBL, KRAS, NRAS are common drivers in pediatric Rasopathies.22
MIRAGE syndrome	The dominant driver gene is the SAMD9 mutation. Additional chromosome aberrations include del(7q).23
SAMD9L-related ATXPC syndrome	The dominant driver gene is the SAMD9L mutation. Additional chromosome aberrations include del(7q).24
ANKRD26-related thrombocytopenia	The dominant driver gene is the ANKRD26 mutation.25