When is myelogenome testing indicated for a patient with a family history of genetic disorders or symptoms suggestive of a myeloid disorder, such as anemia, thrombocytopenia, or leukocytosis?

Myelogenome Testing Indications

Myelogenome testing should be performed in patients with unexplained cytopenias (anemia, thrombocytopenia, or leukocytosis) when there is a family history suggesting inherited myeloid disorders, particularly when first-degree relatives have had leukemia or unexplained hematologic abnormalities, or when the patient presents at a young age with these findings. 1

When to Suspect Familial Myeloid Disorders

Take a thorough three-generation family history focusing on:

• Malignancies in family members, particularly leukemias, myelodysplastic syndromes, or other hematologic cancers 1
• Previous bleeding episodes in relatives, suggesting inherited platelet disorders 1
• Unexplained cytopenias in family members 1
• Young age of onset in the patient (especially under 40 years), which increases suspicion for germline predisposition 1
• Bone marrow failure syndromes in the family, such as Fanconi anemia or dyskeratosis congenita 1

Specific Clinical Scenarios Requiring Germline Testing

Patients with variant allele frequency (VAF) of 40-60% for genes associated with predisposition syndromes should be referred for germline testing, as this suggests a constitutional rather than acquired mutation 1

Young patients with familial cytopenias require additional genetic screening beyond standard somatic mutation testing 1

Patients presenting with specific syndromic features:

• Platelet abnormalities with family history → Test for RUNX1, ANKRD26, or ETV6 germline mutations 1
• Organ system manifestations (immunodeficiency, lymphedema, pulmonary disease) → Test for GATA2 mutations 1
• Recurrent infections or warts → Consider GATA2-related syndrome 1

Recommended Genetic Testing Panel

For suspected familial myeloid disorders, test the following genes: 1

• Myelodysplastic/acute leukemia predisposition syndromes: CEBPA, DDX41, RUNX1, ANKRD26, ETV6, GATA2, SRP72, 14q32.2 genomic duplication (ATG2B/GSKIP)
• Cancer predisposition syndromes: TP53 (Li Fraumeni syndrome), BRCA1/BRCA2
• Bone marrow failure syndromes: TERC, TERT (dyskeratosis congenita), Fanconi anemia genes

Standard Workup Before Genetic Testing

Complete the following baseline evaluation first: 1

• Complete blood count with differential and peripheral smear examination 1
• Bone marrow aspiration with iron stain and biopsy 1
• Conventional cytogenetics (mandatory) 1
• Serum erythropoietin, RBC folate, serum B12, ferritin, iron studies to exclude nutritional causes 1
• Flow cytometry to evaluate for paroxysmal nocturnal hemoglobinuria clone or large granular lymphocytic disease 1
• HIV testing if clinically indicated 1

Critical Pitfalls to Avoid

Do not confuse somatic mutations with germline predisposition. Many older individuals harbor somatic mutations in DNMT3A, TET2, and ASXL1 as part of clonal hematopoiesis of indeterminate potential (CHIP), which does not indicate familial disease 2

Germline testing must be performed in close collaboration with a genetic counselor, as results have implications for family members and reproductive decisions 1

Patients with suspected heritable myeloid neoplasms who test negative for known predisposition genes should be entered into research studies to facilitate discovery of new syndromes 1

Familial AML with germline CEBPA mutations requires identification of biallelic mutations to define the entity and predict favorable outcome; monoallelic CEBPA mutations do not constitute the familial syndrome 1

Therapy-related myeloid neoplasms frequently harbor germline mutations in TP53 and BRCA1/2, so consider germline testing in patients with prior chemotherapy or radiation exposure 1