Table 1.

Most common germline disorders associated with MDS.

Syndromes	Gene	Inheritance	Cellular Function	Associated Phenotype	Evolution to MDS/AML
DC/Telomeropathy	DKC1 [18]	X-linked	Telomere maintenance	Mucocutaneous features (nail dystrophy, skin pigmentation abnormalities, oral leukoplakia) Idiopathic pulmonary fibrosis Liver diseases Immunodeficiency/immune dysregulation Endocrinopathies Osteoporosis, dental abno malities, short stature CNS abnormalities/cerebellar hypoplasia Secondary cancer (oral and gastrointestinal squamous cell carcinoma) [19,20,21,22]	Cumulative incidence of evolution to MDS i creases with age, with a prevalence of 13% in non-transplanted patients [22]
	TERT, TERC, TINF2, RTEL1 ACD/TPP1, PARN, NAF1 STN1	AD
	TERT, WRAP53 NOLA3, NOLA2 TCB1, RTEL1 CTC1, CD/TPP1 PARN, NHP2 NOP10 [23]	AR
FA	FANC (A, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q, R, S, T, U, W)	AR	DNA Repair pathway	Short stature, café au lait, spots and hyper/hypopigmentation, abnormal thumbs, absent radii, microcephaly, micro- ophthalmia, structural renal/urogenital, cardiac malformations abnormalities/malformations, endocrinopathies, hypogonadism, squamous cell carcinoma: oral, gastrointestinal, genitourinary. FANCD1/BRCA2 Subtype: solid tumors and ALL [24,25]	Cumulative incidence of evolution to MDS/AML of 33% by 40 years old [25,26,27]
	FANCB [28]	X-linked
Emberger syndrome MonoMAC syndrome DCML	GATA2 [29,30]	AD	Transcription factor	Emberger syndrome: lymphedema, sensorineural hearing loss and monosomy 7 MonoMAC syndrome: monocytopenia and Mycobacterium avium complex infection DCML: susceptibility to mycobacterial, fungal, viral infections; warts; molluscum; pulmonary alveolar proteinosis [31,32]	Cumulative risk of evolution to MDS/AML: 6% at the age of 10 years, 39% at the age of 20 years, and 81% at the age of 40 years [33,34,35]
SDS	SBDS [36,37]	AR	Biogenesis of ribosomes and mitotic spindle stabilization	Short stature, exocrine pancreatic dysfunction, pancreatic lipomatosis/atresia, skeletal dysplasia, osteopenia, eczema, transient transaminitis/hepatomegaly in early childhood, dental anomalies, immunodeficiencies, endocrinopathies, neurocognitive and other variable congenital anomalies [38]	Cumulative risk of evolution to MDS/AML: 18.8% at 20 years and 36.1% at 30 years of age [39]
MIRAGE syndrome ATXPC/MLSM7	SAMD9 SAMD9L [40,41,42]	AD	Proliferation control	MIRAGE syndrome: cytopenias, immunologic abnormalities, short stature, a renal hypoplasia, invasive bacterial infections, gastrointestinal (chronic diarrhea, genitourinary abnormalities, delay of developmental milestones, intrauterine growth restriction ATXPC: ataxia, cerebellar hypoplasia, invasive bacterial infections, alveolar proteinosis, cytopenia [43,44]	No data on cumulative risk of evolution to MDS/AML
Familiar MDS associated with thrombocytope-nia	RUNX1, ANKRD26, ETV6 [45]	AD	Transcription factor	Thrombocytopenia, platelet dysfunction [46]	Prevalence of MDS and AML is of about 40% in patients with RUNX1, of 8% in patients with ANKRD26 and of 23% in patients with ETV6 [47,48]
DBA	GATA1, RPL5, 9, 11, 15, 18, 26, 27, 31, 35, 35a, RPS7, 10, 15a, 17, 19, 24, 26, 27, 28, 29 [49]	AD	Ribosomopathy	Short stature, severe macrocytic hyporigenerative anemia in infancy, facial dysmorphisms, radial ray anomalies, skeletal anomalies, genitourinary and heart malformations. Neutropenia and immunodeficiencies associated with RPL35a [50]	Cumulative risk of evolution to AML of 2% by 45 years [51]
Severe congenital neutropenia	ELANE [52]	AD	ELANE encodes for neutrophil elastase	Osteopenia	Cumulative risk of evolution to MDS/AML of 22% after 15 years for ELANE [53]
	GFI1			Lymphopenia
	HAX1	AR		Seizures, neurologic abno malities [54]
	G6PC3			Structural heart disease, urogenital anomalies, prominent veins, deafness, skeletal anomalies, immune dysregulation, colitis, poor growth, thrombocytopenia [53]
	JAGN1 [54]			Skeletal, dental anomalies

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; ATXPC, ataxia-pancytopenia syndrome; DBA, Diamond-Blackfan anemia; DC, Dyskeratosis congenita; DCML, dendritic cell, monocyte, B and natural killer (NK) lymphoid deficiency; FA, Fanconi anemia; MDS, myelodysplastic syndromes; MLSM7, myelodysplasia and leukemia syndrome with monosomy 7 syndrome; SDS, Schwachman Diamond syndrome.