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Over six years, 357 patients initially diagnosed with bone marrow failure (BMF) were evaluated, with 152 patients lacking identifiable causes undergoing further analysis. Among these, 53 (34.9%) exhibited features of inherited BMF syndromes, and 13 (24.5%) developed FHM. In a separate cohort of 27 patients with inherited immunodeficiency disorders, 8 (29.6%) developed FHM associated with <jats:italic>NHEJ1<\/jats:italic> or <jats:italic>LYST<\/jats:italic> variants, underscoring the familial clustering of hematologic disorders. Notably, 6 of 7 patients from the same family (family-1) with homozygous <jats:italic>NHEJ1<\/jats:italic> variants progressed to secondary myelodysplastic syndrome (sMDS), acute myeloid leukemia (AML), or lymphoma. Among 780 patients diagnosed with hematological malignancies during the study period, 45 (5.8%) were confirmed to have FHM, with 33 patients enrolled for detailed analysis. Of these, 16 (48.5%) had DNA-repair deficiencies (DNA-RD), including eight with Fanconi anemia, six with <jats:italic>NHEJ1<\/jats:italic> variants, and two with <jats:italic>BRCA2<\/jats:italic> mutations. The remaining 17 patients presented conditions such as familial myeloproliferative neoplasms, dyskeratosis congenita (DC) [<jats:italic>TERT<\/jats:italic>, <jats:italic>DKC1<\/jats:italic> variants], and Chediak-Higashi syndrome. Two siblings (family-3) with a rare <jats:italic>TERT<\/jats:italic> variant and a unique DC phenotype developed sMDS after prolonged BMF. Patients with DNA-RD were younger and exhibited higher rates of growth failure, recurrent infections, and endocrinopathies. These cases frequently progressed to sMDS or AML. A comparative analysis of 319 individuals with DNA double-strand break repair deficiencies revealed a 45% frequency of hematological malignancies. Lymphoma was most common in Nijmegen breakage syndrome (79.4%) while MDS\/AML was prevalent in Cernunnos deficiency (66.6%). The findings emphasize the importance of early diagnosis, genetic testing, and personalized management, including timely transplantation, to improve outcomes in FHM. This research underscores the need for clinical awareness and surveillance to facilitate timely interventions and mitigate disease progression.<\/jats:p>","DOI":"10.1007\/s00277-025-06257-6","type":"journal-article","created":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T09:02:48Z","timestamp":1741251768000},"page":"1633-1653","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Genetic variants in NHEJ1 and related DNA repair disorders: insights into phenotypic heterogeneity and links to hypoplastic myelodysplastic syndromes and familial hematological malignancies susceptibility"],"prefix":"10.1007","volume":"104","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5487-9493","authenticated-orcid":false,"given":"Mahmoud I.","family":"Elbadry","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8976-2989","authenticated-orcid":false,"given":"Elsayed","family":"Abdelkreem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2409-0517","authenticated-orcid":false,"given":"Ahmed","family":"Tawfeek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1518-1791","authenticated-orcid":false,"given":"Go Hun","family":"Seo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7952-3798","authenticated-orcid":false,"given":"Shereen Philip","family":"Aziz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,6]]},"reference":[{"issue":"1","key":"6257_CR1","doi-asserted-by":"crossref","first-page":"28","DOI":"10.3109\/10428194.2012.701738","volume":"54","author":"JE Churpek","year":"2013","unstructured":"Churpek JE, Lorenz R, Nedumgottil S, Onel K, Olopade OI, Sorrell A, Owen CJ, Bertuch AA, Godley LA (2013) Proposal for the clinical detection and management of patients and their family members with familial myelodysplastic syndrome\/acute leukemia predisposition syndromes. 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