Approach to specialized work up of confirmed BMF. Specialized assays can be used for diagnosis of the IBMFS. Chromosome breakage studies for FA are performed by exposing cultured cells (usually peripheral blood lymphocytes) to diepoxybutane (DEB), a DNA cross-linking agents, and seeing how much chromosomal breakage is induced at a concentration of DEB that has little effect on normal cells.⁴²  Testing can be misleading or inconclusive for 2 reasons: 1) somatic reversion in the hematopoietic cells causes a false negative (this can be overcome by testing skin fibroblasts if you have a high clinical suspicion and negative peripheral blood DEB) or 2) recent chemotherapy administration (increase in baseline breakage). Telomere length is assessed in peripheral blood lymphocytes using flow-FISH and reported as a percentile for age. TL in lymphocytes <1st percentile is very sensitive and specific for TBD, ≥1st but <10th percentile is suggestive of possible TBD in the right clinical context, and ≥10th percentile is very unlikely to be TBD.⁴³  High erythroid adenosine deaminase (eADA) enzyme activity levels are found in cases of DBA. Targeted sequencing can identify both germline and somatic variants when peripheral blood is used; to confirm germline status, sequencing of a germline control tissue such as fibroblasts (skin biopsy) or testing of family members should be sought. Interpretation of genetic reports, particularly when VUS is reported, is challenging, and specialist input may be required. Testing for primary immunodeficiency syndromes is pursued when there is a clinical history suggestive of recurrent and/or atypical infections, autoimmunity, or presence of severe lymphopenia. Lymphocyte subsets and serum immunoglobulins are useful in this setting. FISH, fluorescence in situ hybridization; TBD, telomere biology disorder; WES, whole exome sequencing; WGS, whole genome sequencing.