Genetic predisposition to MDS: clinical features and clonal evolution

Abstract

Myelodysplastic syndrome (MDS) typically presents in older adults with the acquisition of age-related somatic mutations, whereas MDS presenting in children and younger adults is more frequently associated with germline genetic predisposition. Germline predisposition is increasingly recognized in MDS presenting at older ages as well. Although each individual genetic disorder is rare, as a group, the genetic MDS disorders account for a significant subset of MDS in children and young adults. Because many patients lack overt syndromic features, genetic testing plays an important role in the diagnostic evaluation. This review provides an overview of syndromes associated with genetic predisposition to MDS, discusses implications for clinical evaluation and management, and explores scientific insights gleaned from the study of MDS predisposition syndromes. The effects of germline genetic context on the selective pressures driving somatic clonal evolution are explored. Elucidation of the molecular and genetic pathways driving clonal evolution may inform surveillance and risk stratification, and may lead to the development of novel therapeutic strategies.

Figure 1.

Selected bone marrow histology and physical findings associated with genetic MDS predisposition syndromes. (A) Hematoxylin and eosin (left panel) or May-Grunwald Giemsa staining of abnormal bone marrow megakaryocytes present in GATA2 predisposition disorders. (B) May-Grunwald Giemsa staining of bone marrow aspirate from a patient with SCN demonstrating myeloid maturation arrest (marrow images courtesy of M. Fleming). (C) Patient features characteristic of diagnostic triad of TBDs, including lacy/reticular pigmentation on neck and trunk, oral leukoplakia, and dystrophic fingernails (images courtesy of S. Agarwal).

Figure 2.

Model of germline genetic context in clonal evolution. Acquired somatic clonal mutations may be adaptive (improve hematopoiesis) or maladaptive (lead to transformation), depending on the underlying genetic MDS predisposition. In SBDS-mutant hematopoietic stem/progenitor cells, iso7q or del20q are common adaptive clonal aberrations, whereas TP53 somatic mutation is maladaptive. Fanconi anemia development of +3q is associated with progression to malignancy, whereas somatic reversion is not. In SAMD9/9L disorders, correction of the mutation by reversion or loss of mutant via truncation is adaptive, whereas development of monosomy is associated with MDS or AML. TERC-mutant HSPCs may undergo somatic reversion to regain 2 wild-type TERC alleles. GOF, gain of function; LOF, loss of function; HSPC, hematopoietic stem/progenitor cells; WT, wild type. Professional illustration by Patrick Lane, ScEYEnce Studios.