Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes

Abstract

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.

Hematopoietic stem cell transplantation in children and adolescents with GATA2-related myelodysplastic syndrome

“…In contrast to older adults, in whom MDS is associated with age-related somatic mutations, MDS in young patients is often associated with genetic syndromes predisposing to myeloid neoplasia. Next to the well-known inherited bone marrow failure syndromes like Fanconi anemia, Shwachman–Diamond syndrome, severe congenital neutropenia, or dyskeratosis congenita, a slew of predisposition syndromes involving genes like GATA2, SAMD9/SAMD9L, RUNX1, ANKRD26, ETV6, SRP72, ERCC6L2 , and others have recently been uncovered [ 1 – 4 ].…”

Neuroinflammation Associated With Inborn Errors of Immunity

“…Heterozygous loss-of-function variants in GATA2 (MIM: 614172) cause a wide range of defects including cytopenias, particularly affecting monocytes, B cells and NK cells, resulting in susceptibility to infections in addition to a risk of developing myelodysplastic syndrome/acute myeloid leukemia ( 232 ). GATA2 is an essential transcription factor for hematopoietic stem/progenitor cell renewal and differentiation ( 233 ).…”

Genetics of Myelodysplastic Syndromes

“…To date, the strongest associations between germline predisposition mutations and development of hematopoietic malignancies are seen for MDS. Germline SAMD9 / SAMD9L mutations are seen in young children [ 53 , 54 ], and about 15% of adolescents and young adults, and up to 40% of patients with monosomy 7, have germline GATA2 mutations [ 55 , 56 ]. In adults diagnosed with MDS from 18 to 40 years old, 19% have germline mutations, commonly in DNA repair and telomere biology genes [ 57 ].…”