Table 1.

Inherited BMF syndromes

Syndrome	Causative genes (inheritance)	Etiology	Clinical manifestations	Frequent chromosomal abnormalities	Frequent somatic mutations
SDS	SBDS (AR)—m/c DNAJC21 (AR) SRP54 (AD) ELF1 (AR)	Ribosomopathy	Hematopoietic/oncologic: neutropenia, anemia, thrombocytopenia, aplastic anemia, MDS, AML Nonhematologic: exocrine pancreatic insufficiency, failure to thrive, malabsorption, short stature, skeletal abnormalities (chondrodysplasia or congenital thoracic dystrophy), endocrine abnormalities, liver dysfunction, cognitive impairment	20q– (interstitial deletion q11.21-q13.32)—loss of EIF6 i(7)(q10)—duplication of hypomorphic SBDS allele High risk: –7/7q– Complex	EIF6—improve ribosome biogenesis and protein translation efficiency High risk: Biallelic TP53—impaired cell cycle checkpoint and apoptosis
FA	FANCA (AR)—m/c FANCB (XR) FANCC (AR) FANCD1/BRCA2 (AR) FANCD2 (AR) FANCE (AR) FANCF (AR) FANCG (AR) FANCI (AR) FANCJ/BRIP1/BACH1 (AR) FANCL (AR) FANCM (AR) FANCN/PALB2 (AR) FANCO/RAD51C (AR) FANCP/SLX4 (AR) FANCQ/ERCC4 (AR) FANCR/RAD51 (AD) FANCS/BRCA1 (AR) FANCT/UBE2T (AR) FANCU/XRCC2 (AR) FANCV/REV7 (AR) FANCW/RFWD3 (AR)	Inability to repair DNA interstrand cross-links	Hematologic/oncologic: thrombocytopenia, anemia, neutropenia, aplastic anemia, MDS, leukemia, squamous cell carcinoma (head and neck, anogenital, esophageal), embryonal tumors (medulloblastoma, neuroblastoma, Wilms tumor in patients with biallelic BRCA2 mutations) Nonhematopoietic: short stature, low birth weight, failure to thrive, microcephaly, microphthalmia, hearing loss, triangular face, micrognathia, cardiac abnormalities (patent ductus arteriosus, atrial septal defect, ventricular septal defect), tracheoesophageal fistula, esophageal atresia, horseshoe or ectopic kidneys, thumb/radius abnormalities, hypoplastic thenar eminence, clinodactyly, café-au-lait spots, hypo/hyperpigmentation of the skin	1q+ High risk: 3q+ –7/7q– Complex Cryptic RUNX1 translocation	Somatic reversion of FANC genes by back mutation, intragenic recombination, second site mutations suppressing the effect of the original mutation, frame-restoring second site insertions and deletions High risk: RUNX1 RAS pathway (KRAS, PTPN11)—(small number of cases)
SCN	ELANE (AD)—m/c HAX1 (AR) GFI1 (AD) G6PC3 (AR) JAGN1 (AR) TCIRG1 (AD) WAS (XR) CSF3R (AD, AR)	Neutrophil maturation arrest and apoptosis	Hematologic/oncologic: severe neutropenia at birth, recurrent infections, MDS, AML	High risk: –7/7q– Complex	CSF3R—enhanced and prolonged response to G-CSF High risk: RUNX1
Short telomere syndrome	TERT (AD, AR)—m/c TERC (AD) DKC1 (XR) NOLA3/NOP10 (AR) NOLA2/NHP2 (AR) TINF2 (AD) WRAP53/TCAB1 (AR) CTC1 (AR) RTEL1 (AD, AR) ACD/TPP1 (AD, AR) PARN (AD, AR) NAF1 (AD) STN1 (AD) NPM1 (AD) ZCCHC8 (AD)	Telomere shortening	Hematologic/oncologic: thrombocytopenia, anemia, neutropenia, pancytopenia, MDS, AML, immunodeficiency, squamous cell carcinoma Nonhematopoietic: the mucocutaneous triad (reticulated skin pigmentation, nail dystrophy, oral leukoplakia), short stature, low birth weight, failure to thrive, hearing loss, retinopathy, mucosal strictures, pulmonary fibrosis, liver fibrosis	High risk: –7/7q– Complex	Somatic reversion— back mutation of DKC1, TERT promoter GOF mutation, mitotic recombination High risk: TP53a
DBA	RPS19 (AD)—m/c RPL3 (AD) RPL5 (AD) RPL7 (AD) RPL11 (AD) RPL14 (AD) RPL15 (AD) RPL18 (AD) RPL19 (AD) RPL23 (AD) RPL26 (AD) RPL27 (AD) RPL31 (AD) RPL35a (AD) RPL36 (AD) PRS7 (AD) RPS8 (AD) RPS10 (AD) RPS15 (AD) RPS17 (AD) RPS24 (AD) RPS26 (AD) RPS27 (AD) RPS27A (AD) RPS28 (AD) RPS29 (AD) GATA1 (XR) TSR2 (XR)	Ribosomopathy; red blood cell aplasia	Hematologic/oncologic: Anemia, reticulocytopenia, MDS, AML, solid tumors (osteogenic sarcoma, lung, colon and cervix) Nonhematologic: low birth weight, growth retardation, developmental delay, short stature, microcephaly, other craniofacial malformation, congenital glaucoma or cataract, strabismus, short neck, thumb abnormalities, horseshoe kidney, hypospadias, cardiac abnormalities	Abnormal cytogenetics infrequent	TP53,a PPM1D, ASXL1 (small number of cases)b
SAMD9/SAMD9L disorders	SAMD9 (AD) SAMD9L (AD)	Growth inhibition	MIRAGE syndrome Hematologic/oncologic: Thrombocytopenia, anemia, MDS with monosomy 7, recurrent infections, bleeding Nonhematologic: intrauterine growth restriction, developmental delay, adrenal hypoplasia, chronic diarrhea, genital anomalies Ataxia-pancytopenia syndrome Hematologic/oncologic: Pancytopenia, anemia, MDS with monosomy 7/del(7q), AML, recurrent infections Nonhematologic: ataxia, cerebellar atrophy, retinal dysfunction, behavioral abnormalities, alveolar proteinosis	–7/7q– 5q–	Somatic reversion by LOF SAMD9 or SAMD9L mutations ETV6, RUNX1, SETBP1 (small number of cases)

^a The differential effects of biallelic vs heterozygous TP53 mutations to leukemic transformation have not been studied in IBMFS other than SDS.

^b Whether somatic mutations contribute to malignant transformation in DBA has not been fully investigated.

m/c, most common; AD, autosomal dominant; AR, autosomal recessive; GOF, gain of function; XR, X-linked recessive.