Figure 4. Model of disease progression.

Progression to advanced disease occurs through multiple different and potentially overlapping mechanisms in patients with MDS or acute leukemia predisposition syndromes. The pathways commonly observed for the different germline predispositions (genes highlighted on the right) are shown. Progression to advanced disease in many predisposition syndromes occurs through a step wise process involving loss of the remaining wild-type allele and acquisition of additional cooperating mutations (top), while others appear to maintain the wild-type allele (middle). SAMD9 and SAMD9L are unique in that disease progression is observed when there is outgrowth of monosomy 7 cells that lack the deleterious germline mutation and then cells can acquire additional somatic mutations for the full disease phenotype.