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. 2025 May;104(5):2693-2706.
doi: 10.1007/s00277-025-06392-0. Epub 2025 May 13.

Clinical usefulness of next-generation sequencing-based target gene sequencing in diagnosis of inherited bone marrow failure syndrome

Young Dai Kwon  1   2 , Kyung Taek Hong  3   4 , Juyeon Lee  1   2 , Yoon Sunwoo  1   2 , Yeseul Kim  5 , Sung Im Cho  5 , Hyun Jin Park  1   2 , Bo Kyung Kim  1   2 , Jee-Soo Lee  5 , Jung Yoon Choi  1   2 , Moon-Woo Seong  2   5 , Hyoung Jin Kang  1   2   6
Affiliations

Clinical usefulness of next-generation sequencing-based target gene sequencing in diagnosis of inherited bone marrow failure syndrome

Young Dai Kwon et al. Ann Hematol. 2025 May.

Abstract

Inherited bone marrow failure syndromes are genetic hematologic disorders with increased cancer risk. Accurate diagnosis is crucial for appropriate management. This study assessed the clinical usefulness of next-generation sequencing (NGS)-based target gene sequencing in pediatric and AYA (adolescent and young adult) patients with hematologic abnormalities. From December 2019 to June 2023, 93 patients with suspected congenital hematologic diseases at a single institution underwent NGS-based testing. Medical records were retrospectively reviewed. The median age at diagnosis was 9.3 years (range 0.2-31.4), with 59.1% males. Indications for testing included specific medical histories (28 patients), persistent cytopenia or recurrent neutropenic fever (22 patients), changes in cytopenia patterns (11 patients), and other reasons (32 patients). Pathogenic variants were identified in 9/28 (32.1%), 3/22 (13.6%), 4/11 (36.4%), and 0/32 (0%). Overall, 16 patients (17.2%) had pathogenic variants, including FANCA, BRCA2, PMS2, ELANE, G6PC3 and VPS13B in patients with idiopathic neutropenia, and GATA2 in patients with suspected myelodysplastic syndrome. Genetic findings led to diagnostic revisions in 12 patients (12.9%), including reclassification of aplastic anemia (AA) as Fanconi anemia, Diamond-Blackfan anemia, or Shwachman-Diamond syndrome, prompting hematopoietic stem cell transplantation and altering cancer surveillance. Pathogenic variants were more frequently observed in patients with a specific medical history or changes in cytopenia, and in those with additional clinical features (cytogenetic abnormalities or non-severe AA). This study demonstrated the diagnostic usefulness of NGS-based target gene sequencing for pediatric and AYA patients with suspected genetic hematologic disorders, supporting the need for multicenter studies and standardized guideline development.

Keywords: Cytopenia; Inherited bone marrow failure syndrome; Next-generation sequencing.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study was approved by the Institutional Review Board of the Seoul National University Hospital (IRB number: 2306-177-1443). As this study involved only a review of medical records and no additional interventions for patients, the requirement for written consent was waived. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Patient selection and testing outcomes in suspected Inherited bone marrow failure syndromes. NGS = next-generation sequencing, IBMFS = inherited bone marrow failure syndromes, AA = aplastic anemia, MDS = myelodysplastic syndromes
Fig. 2
Fig. 2
Distribution of pathogenic variants and variants of unknown significance (VUS) in 93 patients. A The horizontal axis category represents presumed diagnoses of the patients at the time of next-generation sequencing-based target gene sequencing. Non-severe AA is categorized within the cytopenia (affecting ≥ 2 lineages) group. HM includes acute lymphoblastic leukemia and acute myeloid leukemia, while Others include hemophagocytic lymphohistiocytosis, Langerhans cell histiocytosis, and other conditions such as isolated anemia. Dark green indicates pathogenic variants, black diamonds (◆) represent carriers of pathogenic variants, and light mint green denotes cases with variants of uncertain significance (VUS) (B) Frequency and patterns of 16 pathogenic variants identified in 93 patients. MDS = myelodysplastic syndromes, HM = hematologic malignancy, AA = aplastic anemia
See this image and copyright information in PMC

References

    1. Erlacher M, Strahm B (2015) Missing Cells: Pathophysiology, Diagnosis, and Management of (Pan)Cytopenia in Childhood. Front Pediatr 3:64. 10.3389/fped.2015.00064 - PMC - PubMed
    1. Giudice V, Cardamone C, Triggiani M, Selleri C (2021) Bone Marrow Failure Syndromes, Overlapping Diseases with a Common Cytokine Signature. Int J Mol Sci 22(2):705. 10.3390/ijms22020705 - PMC - PubMed
    1. Lee JM, Kim HS, Yoo J, Lee J, Ahn A, Cho H, Han EH, Jung J, Yoo JW, Kim S, Lee JW, Cho B, Chung NG, Kim M, Kim Y (2024) Genomic insights into inherited bone marrow failure syndromes in a Korean population. Br J Haematol 205(4):1581–1589. 10.1111/bjh.19509 - PubMed
    1. Park M (2022) Overview of inherited bone marrow failure syndromes. Blood Res 57(S1):49–54. 10.5045/br.2022.2022012 - PMC - PubMed
    1. Gálvez E, Vallespín E, Arias-Salgado EG, Sánchez-Valdepeñas C, Giménez Y, Navarro S, Río P, Bogliolo M, Pujol R, Peiró M, Nevado J, Zubicaray J, Sebastián E, Catalá A, Beléndez C, Díaz de Heredia C, Galera A, Badell I, Madero L, Perona R, Sastre L, Surrallés J, Bueren J, Lapunzina P, Sevilla J (2021) Next-generation sequencing in bone marrow failure syndromes and isolated cytopenias: Experience of the Spanish Network on Bone Marrow Failure Syndromes. Hemasphere 5(4). 10.1097/HS9.0000000000000539 - PMC - PubMed

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