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  • The Role of Covert Germline Predisposition and Polygenic Susceptibility in Pediatric Acute Lymphoblastic Leukemia and Their Clinical Implications

  • Reyhaneh Ashjari Aghdam ,1,*
    1. B.Sc. Graduate in Cell and Molecular Biology, Islamic Azad University, Tabriz Branch, Tabriz, Iran


  • Introduction: Pediatric acute lymphoblastic leukemia (pALL) is the most common childhood malignancy. Its etiology combines somatic driver lesions with inherited genetic susceptibility. Classic cancer-predisposition syndromes demonstrate high-penetrance germline risk, yet reliance on overt phenotype or family history underestimates the contribution of inherited factors. Covert germline predisposition—pathogenic variants occurring without clear syndromic features—and common low-effect variants that generate polygenic susceptibility extend risk beyond recognizable Mendelian entities. Genetic susceptibility to pALL is therefore best viewed as a continuum. This narrative review synthesizes evidence on the contribution of covert predisposition and polygenic background and their clinical implications.
  • Methods: Peer-reviewed literature was identified in PubMed/MEDLINE, Web of Science, Scopus and Google Scholar, prioritizing 2018–2026 publications while retaining landmark earlier studies. Search terms combined pediatric or childhood ALL with germline predisposition, covert predisposition, rare and common germline variants, GWAS and polygenic risk. Studies addressing germline susceptibility or clinical implications in pediatric ALL were included; purely somatic or non-peer-reviewed reports were excluded. Evidence was synthesized narratively. No systematic review or quantitative meta-analysis was performed.
  • Results: Germline susceptibility to pALL spans overt predisposition syndromes and covert pathogenic variants, including alterations in ETV6, IKZF1, PAX5, RUNX1 and TP53. Stoltze et al. (Leukemia 2025) identified seven overt and six predominantly covert genetic causes, highlighting the limitations of phenotype- and family-history-based testing. Common variants at loci such as ARID5B, IKZF1, CEBPE, GATA3 and the BMI1–PIP4K2A region contribute cumulatively to polygenic susceptibility. Polygenic risk scores show research-level potential but remain limited by ancestry dependence and incomplete validation. Emerging evidence suggests interaction between rare and common variants. Clinically, germline findings may inform genetic counseling, surveillance, treatment planning and donor selection, whereas TPMT and NUDT15 primarily represent pharmacogenomic variation.
  • Conclusion: Inherited susceptibility to pALL forms a continuum spanning overt high-penetrance syndromes, covert germline predisposition and common-variant polygenic background. The strongest clinical-genetics evidence supports the classic syndromes and high-penetrance transcription-factor genes. Covert predisposition represents an important and increasingly recognized contributor that may warrant broader germline assessment. Polygenic risk scores remain research tools pending further multi-ancestry validation. Recognition of this multi-layered architecture is essential for precision risk assessment, counseling and care in pediatric ALL.
  • Keywords: Pediatric ALL; Germline risk; Polygenic risk; Genetic variants; Cancer genetics

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