Diagnostic evaluation and considerations in hypocellular bone marrow failure—A focus on genomics

Abstract

Hypocellular bone marrow failure (BMF) has myriad differential diagnoses, most simply considered as acquired and inherited disorders, which are frequently indistinguishable upon morphologic examination of the blood and bone marrow. Accurate diagnosis is critical to optimization of management and begins with a detailed history (including family history) and physical examination. Next‐generation sequencing technologies complement traditional testing techniques (such as chromosomal fragility and telomere length assessment) and have a broad application in the diagnosis and prognostication of BMF, with the importance of detection of both germline changes and also somatic variants increasingly well understood and appreciated. There is increasing awareness of germline predisposition to haematological malignancy, which incorporates but is not limited to the traditional inherited BMF syndromes and which raises challenges for counselling, monitoring and treatment of people who harbour a germline lesion. There are many benefits to both patients and their kindred of accurate determination of the precise germline change underlying heritable bone marrow diseases, along with its associated mode of inheritance. While individually, these diseases are rare, collectively they are not so and there are many collaborative efforts underway to document the natural history of these disorders, the associated phenotypes and the ever‐increasing list of variants which have sufficient evidence to warrant the ascription of a pathogenic classification. We describe the many diagnostic considerations when evaluating newly presenting patients with hypocellular BMF, with a focus on genomic assessment, which is relevant in both germline and acquired diseases.

Diagnostic work‐up for severe aplastic anemia in children: Consensus of the North American Pediatric Aplastic Anemia Consortium

“…A NAPAAC MDS Working Group survey showed NAPAAC centers universally perform conventional metaphase cytogenetics though varied in which specific FISH testing was ordered 16 . Based upon the association with specific IBMFS and known etiologies of pediatric MDS, we recommend that, at a minimum, FISH includes evaluation for 7/del(7q), −5/del(5q), +8, and del (20q) 17–20 . Monosomy 7 in a child should prompt evaluation for germline mutations in genes such as SAMD9/SAMD9L or GATA2 .…”

“…Monosomy 7 in a child should prompt evaluation for germline mutations in genes such as SAMD9/SAMD9L or GATA2 . Monosomy 7 has also been reported in Fanconi Anemia (FA), Dyskeratosis Congenita (DC), and Shwachman Diamond Syndrome (SDS) 20 . Clonal cytogenetic abnormalities arising in patients with FA who progressed to MDS or acute myeloid leukemia (AML) include 1q+, 3q+, −7/del7q, and 11q.…”

“…Monosomy 7 has also been reported in Fanconi Anemia (FA), Dyskeratosis Congenita (DC), and Shwachman Diamond Syndrome (SDS). 20 Clonal cytogenetic abnormalities arising in patients with FA who progressed to MDS or acute myeloid leukemia (AML) include 1q+, 3q+, À7/del7q, and 11q. The 1q + and del20q are also observed in patients with or without MDS or AML.…”

The impact of clonal hematopoiesis on outcomes in patients with aplastic anemia

“…Several genetic disorders including Schwachman-Diamond syndrome (which leads to a reduction in hematopoietic stem cells' ability to repair DNA because of genetic lesions), congenital amegakaryocytic thrombocytopenia (MPL gene), Diamond Blackfan anemia (SBDF gene), Fanconi anemia, some GATA2 spectrum disorders, congenital keratosis, SRP72, and congenital pure red cell aplasia have all been identified as familiar cases of AA [29][30][31][32][33][34]. Careful history--taking and physical examinations may be helpful in the identification of germ-like genetic bone marrow failure disorders associated with AA and included in differential diagnostics in children, adolescents and young adults (Table IV) [6,35]. Next-generation sequencing technologies have facilitated the discovery of mutations that cause pancytopenia and lead to aplastic anemia.…”

Optical Genome Mapping as a New Tool to Overcome Conventional Cytogenetics Limitations in Patients with Bone Marrow Failure

“…On the one hand, at diagnosis, karyotype abnormalities may have prognostic significance or even provide diagnostic clues for suspicion of germline variants (such as monosomy 7 in SAMD9/SAMD9L syndromes). On the other hand, they are important in the follow-up for monitorization of clonal evolution and transformation [1].…”