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

Best Pract Res Clin Haematol. 2020 Sep;33(3):101197. doi: 10.1016/j.beha.2020.101197. Epub 2020 Jul 29.

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 paediatric 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, SAMD9/9L disorders show incomplete penetrance with various clinical outcomes ranging from spontaneous haematological remission observed in young children to malignant progression.

Keywords: GATA2; Germline predisposition; Hereditary MDS; SAMD9; SAMD9L.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Chromosome Deletion
  • Chromosomes, Human, Pair 7 / metabolism
  • GATA2 Deficiency* / diagnosis
  • GATA2 Deficiency* / genetics
  • GATA2 Deficiency* / therapy
  • GATA2 Transcription Factor / genetics
  • Genetic Predisposition to Disease*
  • Germ-Line Mutation*
  • Hematologic Neoplasms* / diagnosis
  • Hematologic Neoplasms* / genetics
  • Hematologic Neoplasms* / therapy
  • Humans
  • Intracellular Signaling Peptides and Proteins / deficiency*
  • Myeloproliferative Disorders* / diagnosis
  • Myeloproliferative Disorders* / genetics
  • Myeloproliferative Disorders* / therapy
  • Syndrome
  • Tumor Suppressor Proteins / genetics*

Substances

  • GATA2 Transcription Factor
  • GATA2 protein, human
  • Intracellular Signaling Peptides and Proteins
  • SAMD9 protein, human
  • SAMD9L protein, human
  • Tumor Suppressor Proteins

Supplementary concepts

  • Chromosome 7, monosomy