Sterile alpha motif domain protein 9 (SAMD9) and its paralogue SAMD9-like (SAMD9L) are cytoplasmic proteins encoded by two juxtaposed single-exon genes on chromosome 7q21. They share a 60% amino acid sequence identity and likely originated from a duplication of a common ancestral gene 1 . Their function remains enigmatic; they have been linked to tumor suppression 2 , inflammation 3 , stress response 4 , development 4 , endosomal fusion 5,6 and protein translation 7,8 . Both proteins were also shown to function as restriction factors forming a cross-species barrier for poxvirus infection [9][10][11][12] . Structural analysis of these large proteins has been limited to homology modeling, which predicted identical domains in either protein (SAM, ALBA2, SIR2, P-loop/ NTPase and OB-fold) 13 . Moreover, these genes exhibit tight regulation during embryonic development and transition to ubiquitous expression levels in adult tissues 14,15 .Notably, Samd9l-haploinsufficient mice develop myeloid neoplasia mimicking human MDS with monosomy 7 5 . Several groups reported germline SAMD9 or SAMD9L mutations (SAMD9/9L mut ) underlying new human syndromes with a propensity for cytopenia, bone marrow failure (BMF) and MDS with non-random monosomy 7 or deletion of 7q 6,16-28 . SAMD9 mutations (SAMD9 mut ) were initially linked to a fatal, early-onset MIRAGE syndrome (myelodysplasia, infections, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy) 6,29 . In contrast, SAMD9L mutations (SAMD9L mut ) were originally described in families with a progressive neurological phenotype, multi-lineage cytopenia and bone marrow hypoplasia (ataxia-pancytopenia syndrome) 16,17 . Recent reports broadened this spectrum and found missense SAMD9/9L mut in non-syndromic familial MDS [30][31][32][33] , truncating SAMD9L mut in children with autoinflammatory panniculitis resembling CANDLE

Increasing awareness about germline predisposition and the widespread application of unbiased whole exome sequencing contributed to the discovery of new clinical entities with high risk for the development of haematopoietic malignancies. The revised 2016 WHO classification introduced a novel category of “myeloid neoplasms with germline predisposition” with GATA2 , CEBPA , DDX41 , RUNX1 , ANKRD26 , and ETV6 genes expanding the spectrum of hereditary myeloid neoplasms (MN). Since then, more germline causes of MN were identified, including SAMD9 , SAMD9L , and ERCC6L2 . This review describes the genetic and clinical spectrum of predisposition to MN. The main focus lies in delineation of phenotypes, genetics and management of GATA2 deficiency and the novel SAMD9/SAMD9L-related disorders. Combined, GATA2 and SAMD9/SAMD9L (SAMD9/9L) syndromes are recognized as most frequent causes of primary pediatric myelodysplastic syndromes, particularly in setting of monosomy 7. To date, ∼550 cases with germline GATA2 mutations, and ∼130 patients with SAMD9/9L mutations had been reported in literature. GATA2 deficiency is a highly penetrant disorder with a progressive course that often rapidly necessitates bone marrow transplantation. In contrast, SAMD9/SAMD9L disorders show incomplete penetrance with various clinical outcomes ranging from spontaneous haematological remission observed in young children to malignant progression.

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