Genomic insights into inherited bone marrow failure syndromes: a single-center clinical study

Abstract

Aim: Inherited Bone Marrow Failure Syndromes (IBMFS) are increasingly diagnosed in both pediatrics and adults presenting with cytopenias, myelodysplastic syndrome, and acute leukemia due to increased awareness among providers. Given the multi-organ involvement in IBMFS, the referrals for genetic testing have extended to individuals with pulmonary fibrosis, liver cirrhosis, and concerns for cancer predisposition in other solid tumors. The purpose of this study is to highlight the real-world data of genetic testing in an Inherited Bone Marrow Failure clinic and the challenges faced.

Method: Patients who were referred to the Medical Genetics and Genomics Outpatient Clinic for evaluation of a suspected underlying IBMFS at the University of Iowa from January 2023 to September 2024 were enrolled in this study. Clinical phenotypes, reasons for referrals, and genetic testing results were recorded and analyzed.

Result: A total of 16 individuals from 15 families were enrolled in this study during this period. Clinical-grade genetic testing yielded a diagnosis in 50% of the patients, with a predominance of patients diagnosed with a telomere biology disorder.

Conclusion: Early diagnosis of an underlying IBMFS is important to reduce mortality and morbidity. Genomic testing is crucial to provide an accurate diagnosis and appropriate management, including donor selection when hematopoietic stem cell transplant is a treatment option.

Keywords

Inherited bone marrow failure syndromes / myelodysplastic syndrome / acute leukemia / pulmonary fibrosis / liver cirrhosis / cancer predisposition to solid tumors

References

[1] GermeshausenM.Congenital amegakaryocytic thrombocytopenia - not a single disease.Best Pract Res Clin Haematol2021;34:101286

[2] IolasconA,RussoR.Congenital dyserythropoietic anemias.Blood2020;136:1274-83

[3] DobrewaW,Bąbol-PokoraK,MłynarskiW.Congenital neutropenia: from lab bench to clinic bedside and back.Mutat Res Rev Mutat Res2024;793:108476

[4] RevyP,BertuchAA.Genetics of human telomere biology disorders.Nat Rev Genet2023;24:86-108

[5] TummalaH,BadatM.The evolving genetic landscape of telomere biology disorder dyskeratosis congenita.EMBO Mol Med2024;16:2560-82 PMCID:PMC11473520

[6] BoussionS,JourdainAS.TAR syndrome: clinical and molecular characterization of a cohort of 26 patients and description of novel noncoding variants of RBM8A.Hum Mutat2020;41:1220-5

[7] Da CostaL,David-NGuyenL.Diamond-blackfan anemia, the archetype of ribosomopathy: how distinct is it from the other constitutional ribosomopathies?.Blood Cells Mol Dis2024;106:102838

[8] KawashimaN,CipolliM,CoreySJ.Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants.Haematologica2023;108:2594-605 PMCID:PMC10543188

[9] BhandariJ,KilleenRB.Fanconi anemia. Treasure Island: StatPearls Publishing; 2024.

[10] DokalI.Inherited bone marrow failure syndromes.J Hematopathol2011;4:53-60

[11] LeeJM,YooJ.Genomic insights into inherited bone marrow failure syndromes in a Korean population.Br J Haematol2024;205:1581-9

[12] Gutierrez-RodriguesF,GroarkeEM.When to consider inherited marrow failure syndromes in adults.Hematol Am Soc Hematol Educ Program2023;2023:548-55 PMCID:PMC10727017

[13] FoxLC,FirkinF.The Australian aplastic Anaemia and other bone marrow failure syndromes registry.Best Pract Res Clin Haematol2023;36:101516

[14] Leal-AnayaP,Yanez-FelixAL.Inherited bone marrow failure syndromes: phenotype as a tool for early diagnostic suspicion at a major reference center in Mexico.Front Genet2023;14:1293929 PMCID:PMC10848162

[15] ParkM.Overview of inherited bone marrow failure syndromes.Blood Res2022;57:49-54 PMCID:PMC9057667

[16] DengJ.Inherited bone marrow failure syndromes: a review of current practices and potential future research directions.Curr Opin Pediatr2023;35:75-83 PMCID:PMC9812861

[17] GroarkeEM,LiuJM.Cell senescence and malignant transformation in the inherited bone marrow failure syndromes: overlapping pathophysiology with therapeutic implications.Semin Hematol2022;59:30-7 PMCID:PMC9062194

[18] LiptonJM,DesaiP,EllisSR.Early onset colorectal cancer: an emerging cancer risk in patients with diamond Blackfan anemia.Genes2021;13:56 PMCID:PMC8774389

[19] SchratzKE,DanoffSK.Cancer spectrum and outcomes in the Mendelian short telomere syndromes.Blood2020;135:1946-56 PMCID:PMC7256360

[20] AlterBP,SavageSA.Cancer in the national cancer institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up.Haematologica2018;103:30-9 PMCID:PMC5777188

[21] KeelSB,Sanchez-BonillaM.Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients.Haematologica2016;101:1343-50 PMCID:PMC5394862

[22] GálvezE,Arias-SalgadoEG.Next-generation sequencing in bone marrow failure syndromes and isolated cytopenias: experience of the spanish network on bone marrow failure syndromes.Hemasphere2021;5:e539 PMCID:PMC7951136

[23] GhemlasI,ZlateskaB.Improving diagnostic precision, care and syndrome definitions using comprehensive next-generation sequencing for the inherited bone marrow failure syndromes.J Med Genet2015;52:575-84

[24] ZhangMY,WalshT.Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity.Haematologica2015;100:42-8 PMCID:PMC4281311

[25] MuramatsuH,YoshidaK.Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes.Genet Med2017;19:796-802

[26] BluteauO,LeblancT.A landscape of germ line mutations in a cohort of inherited bone marrow failure patients.Blood2018;131:717-32

[27] BlomberyP,RylandGL.Utility of clinical comprehensive genomic characterization for diagnostic categorization in patients presenting with hypocellular bone marrow failure syndromes.Haematologica2021;106:64-73 PMCID:PMC7776333

[28] GoodwinS,McCombieWR.Coming of age: ten years of next-generation sequencing technologies.Nat Rev Genet2016;17:333-51 PMCID:PMC10373632

[29] KulasekararajA,DokalI.Guidelines for the diagnosis and management of adult aplastic anaemia: a British society for haematology guideline.Br J Haematol2024;204:784-804

[30] ShimanoKA,RoseMJ.Diagnostic work-up for severe aplastic anemia in children: consensus of the North American pediatric aplastic anemia consortium.Am J Hematol2021;96:1491-504

[31] RoyNBA,RussoR.The use of next-generation sequencing in the diagnosis of rare inherited anaemias: a joint BSH/EHA good practice paper.Hemasphere2022;6:e739 PMCID:PMC9170004

[32] KhouryJD,AblaO.The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms.Leukemia2022;36:1703-19

[33] DöhnerH,AppelbaumFR.Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN.Blood2022;140:1345-77

[34] ArberDA,HasserjianRP.International consensus classification of myeloid neoplasms and acute leukemia: integrating morphologic, clinical, and genomic data.Blood2022;140:1200-28

[35] GreenbergPL,Al-KaliA.NCCN guidelines® insights: myelodysplastic syndromes, version 3.2022.J Natl Compr Canc Netw2022;20:106-17

[36] FeursteinS,MehtaN.A practical guide to interpreting germline variants that drive hematopoietic malignancies, bone marrow failure, and chronic cytopenias.Genet Med2022;24:931-54

[37] Gutierrez-RodriguesF,WlodarskiMW.Somatic mosaicism in inherited bone marrow failure syndromes.Best Pract Res Clin Haematol2021;34:101279 PMCID:PMC8374086

[38] SchratzKE,CosnerZL.Somatic reversion impacts myelodysplastic syndromes and acute myeloid leukemia evolution in the short telomere disorders.J Clin Invest2021;131:e147598 PMCID:PMC8439599

[39] TrottierAM.Inherited predisposition to haematopoietic malignancies: overcoming barriers and exploring opportunities.Br J Haematol2021;194:663-76

[40] McReynoldsLJ,WangY.Genetic testing in severe aplastic anemia is required for optimal hematopoietic cell transplant outcomes.Blood2022;140:909-21 PMCID:PMC9412004

[41] AgarwalS.Minimal intensity conditioning strategies for bone marrow failure: is it time for "preventative" transplants?.Hematol Am Soc Hematol Educ Program2023;2023:135-40 PMCID:PMC10727038

[42] AlterBP.Inherited bone marrow failure syndromes: considerations pre- and posttransplant.Hematol Am Soc Hematol Educ Program2017;2017:88-95 PMCID:PMC6142586

[43] AtmarK,HooimeijerL.Diagnostic value of a protocolized in-depth evaluation of pediatric bone marrow failure: a multi-center prospective cohort study.Front Immunol2022;13:883826 PMCID:PMC9094492

[44] BonfimC.Special pre- and posttransplant considerations in inherited bone marrow failure and hematopoietic malignancy predisposition syndromes.Hematol Am Soc Hematol Educ Program2020;2020:107-14 PMCID:PMC7727534

[45] DietzAC,VlachosA.Current knowledge and priorities for future research in late effects after hematopoietic cell transplantation for inherited bone marrow failure syndromes: consensus statement from the second pediatric blood and marrow transplant consortium international conference on late effects after pediatric hematopoietic cell transplantation.Biol Blood Marrow Transplant2017;23:726-35 PMCID:PMC5423755

[46] DietzAC,VlachosA.Late effects screening guidelines after hematopoietic cell transplantation for inherited bone marrow failure syndromes: consensus statement from the second pediatric blood and marrow transplant consortium international conference on late effects after pediatric HCT.Biol Blood Marrow Transplant2017;23:1422-8 PMCID:PMC5565711

[47] HuddaZ.Posttransplant complications in patients with marrow failure syndromes: are we improving long-term outcomes?.Hematol Am Soc Hematol Educ Program2023;2023:141-8 PMCID:PMC10727016

[48] RichardsS,BaleS.Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med2015;17:405-24 PMCID:PMC4544753

[49] RiggsER,CherryAM.Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen).Genet Med2020;22:245-57

[50] AlderJK,StrongMA.Diagnostic utility of telomere length testing in a hospital-based setting.Proc Natl Acad Sci USA2018;115:E2358-65

[51] ManickamK,DemmerLA.Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG).Genet Med2021;23:2029-37

[52] GodleyLA,BoltonK.Germline predisposition in hematologic malignancies: testing, management, and implications.Am Soc Clin Oncol Educ Book2024;44:e432218

[53] PadronE,TeerJK.Germ line tissues for optimal detection of somatic variants in myelodysplastic syndromes.Blood2018;131:2402-5 PMCID:PMC5969383

[54] Ceyhan-BirsoyO,RanaS.Universal germline genetic testing in patients with hematologic malignancies using DNA isolated from nail clippings.Haematologica2024;109:3383-90 PMCID:PMC11443390

[55] StewartBL,BannonSA.Risk assessment and genetic counseling for hematologic malignancies-Practice resource of the National Society of Genetic Counselors.J Genet Couns2025;34:e1959

[56] MaK,NgKK.Saturation mutagenesis-reinforced functional assays for disease-related genes.Cell2024;187:6707-24.e22 PMCID:PMC11568926

[57] SanchezSE,WangY.Digital telomere measurement by long-read sequencing distinguishes healthy aging from disease.Nat Commun2024;15:5148 PMCID:PMC11189511

[58] ThamCY,YanT.High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform.Nat Commun2023;14:281 PMCID:PMC9845338

[59] SholesSL,GershmanA,TimpW.Chromosome-specific telomere lengths and the minimal functional telomere revealed by nanopore sequencing.Genome Res2022;32:616-28 PMCID:PMC8997346

[60] SmirnovD,ProkischH.Integrative omics approaches to advance rare disease diagnostics.J Inherit Metab Dis2023;46:824-38

[61] MarwahaS,AshleyEA.A guide for the diagnosis of rare and undiagnosed disease: beyond the exome.Genome Med2022;14:23 PMCID:PMC8883622

[62] MontgomerySB,WheelerMT.Toward transcriptomics as a primary tool for rare disease investigation.Cold Spring Harb Mol Case Stud2022;8:a006198 PMCID:PMC8958920

[63] CummingsBB,TukiainenT.Improving genetic diagnosis in Mendelian disease with transcriptome sequencing.Sci Transl Med2017;9:eaal5209

[64] ZechM,SkorvanekM.Combined genomics and proteomics unveils elusive variants and vast aetiologic heterogeneity in dystonia.Brain2025;awaf059

[65] MusunuruK,ColeFS.Functional assays to screen and dissect genomic hits: doubling down on the national investment in genomic research.Circ Genom Precis Med2018;11:e002178 PMCID:PMC5901889

[66] OlijnikAA,WongZC.Generating human bone marrow organoids for disease modeling and drug discovery.Nat Protoc2024;19:2117-46

[67] Frenz-WiessnerS,BuserM.Generation of complex bone marrow organoids from human induced pluripotent stem cells.Nat Methods2024;21:868-81 PMCID:PMC11093744