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Germline predisposition for MDS

  • With the use of next generation sequencing (NGS) an increasing number of germline conditions predisposing individuals to myeloid malignancies and bone marrow failure have been identified.
  • The most common germline conditions are point mutations and deletions. 
  • Some conditions, such as germline mutations in GATA2 and RUNX1 may also be detected by NGS platforms aimed at detecting somatic mutations. Germline variants should be suspected when variant allele fraction (VAF) is around 0.5 or greater.
  • Other conditions need specialized methods, e.g. to assess telomere length or detect deletions, and clinical genetic laboratories are increasingly using whole genome sequencing in the diagnostic process .
  • Knowledge about a germline condition may be very important in the planning of treatment, e.g. stem cell transplant (SCT), in an individual patient.
  • For details, see Table 7.02 of the WHO 2016 classification of Tumours of Haematopoetic and Lymphoid Tissues.

MDS-RIGHT recommendations for screening for germline mutations with predisposition to myeloid neoplasms

  • Early contact with a specialised center or clinical genetics department is usually indicated in case of suspected germline conditions. Patients should be offered genetic counselling before genetic screening.
  • The following MDS patient categories should be considered for, investigation of germline conditions and a careful 3-generational family history taken
    • <30 years with a clear diagnosis of MDS
    • Family history of hematological malignancy and / or solid tumour consistent with germline predisposition (WHO 2016 - Table 7.02)
    • Family history of thrombocytopenia or platelet disorders
    • History or physical signs suspected for inherited syndrome with predisposition to myeloid neoplasm (WHO 2016 - Table 7.02)
    • Young patients with medical history of multiple tumors, prolonged history of cytopenia, or hypoplastic bone marrow.
  • Desai AV, Perpich M, Godley LA.. Clinical Assessment and Diagnosis of Germline Predisposition to Hematopoietic Malignancies: The University of Chicago Experience. Front Pediatr. 2017 Dec 6;5:252..PMID:29270394