Testing for Inherited Bone Marrow Failure May Be Unnecessary in Severe Aplastic Anemia

Delaying treatment for severe aplastic anemia (SAA) until genetic testing for inherited bone marrow failure syndromes (IBMFS) is completed may be detrimental in patients with SAA with negative workup and history, according to a retrospective study presented at the 2024 American Society of Pediatric Hematology/Oncology Conference.

In the analysis, however, “two patients with concerning history at presentation were found to have possible IBMFS,” reported lead author, Jill de Jong, MD, PhD, of the University of Chicago, “indicating that genetic testing is indicated for patients with positive findings on standard comprehensive diagnostic workup.”

Genetic Testing Unnecessary in Severe Aplastic Anemia Population

The study enrolled 151 pediatric and young patients with idiopathic SAA diagnosed per Camitta criteria whose laboratory work-up for chromosome breakage testing, physical exam, and past medical and family history were not suggestive of an IBMFS. Blood or bone marrow samples underwent exome sequencing and sequencing results were then evaluated for variants in 94 genes associated with IBMFS.

Overall, 1,020 variants were identified, and the researchers categorized 958 (93.9%) as benign or likely benign, 57 (5.6%) as variants of uncertain significance, and five (0.5%) as pathogenic or likely pathogenic. Two patients had pathogenic variants in genes associated with IBMFS whose histories were retrospectively found to be suggestive of IBMFS at the time of SAA diagnosis.

One patient had two pathogenic variants of the FANCC gene, though the authors noted the zygosity of these variants was still undergoing analysis. They commented that Fanconi anemia was unlikely as the patient had no unexpected toxicity while undergoing hematopoietic stem cell transplantation with standard conditioning.

A second patient had two pathogenic variants in ERCC6L2 and developed progressive cytopenias over five months. A third patient had a missense pathogenic variant in SAMD9L, and the authors noted he had paternal family history of an uncertain neurodegenerative disorder consistent with pancytopenia-ataxia syndrome.

Reference

De Jong J, Gaviria M, Koppayi A, et al. Genetic testing for inherited bone marrow failure in pediatric patients with severe aplastic anemia. Poster #58. Presented at the 2024 American Society of Pediatric/Hematology Oncology Conference; April 3-6, 2024; Seattle, Washington.