Low frequency and rare coding variants affect susceptibility and progression of childhood acute lymphoblastic leukemia.

[UNLABELLED] This study aimed to explore the potential genetic underpinnings of childhood acute lymphoblastic leukemia (ALL). Initially, an exome-wide association analysis of 89 ALL survivors and 356 controls was conducted to identify candidate genes, incorporating single-variant tests and annotation-weighted aggregation tests. Single-cell analyses characterized the candidate genes’ biological context, while aggregate testing linked these genes to clinical traits in survivors, along with bulk tissue transcriptomes profiling their expression patterns in relation to secondary adverse events (e.g., progression, relapse, secondary malignant neoplasms or death). Results from single-variant tests showed that rs57421986 of hematology-related gene exhibited a suggestive association with ALL [minor allele frequency = 0.029, odds ratio (OR) = 21.7,  = 5.86 × 10]. Aggregation tests of low-frequency and rare variants identified ( = 3.97 × 10), ( = 4.18 × 10), ( = 2.46 × 10), and ( = 2.20 × 10) as ALL-associated genes. Notably, and demonstrated differential expression across diverse immune cells between incident cases and controls. Clinical phenome analyses linked to mean corpuscular hemoglobin ( = 4.32 × 10), alkaline phosphatase ( = 4.33 × 10), and free triiodothyronine ( = 4.85 × 10), to red blood cell count ( = 2.83 × 10) and mean corpuscular volume ( = 2.04 × 10), and to thyroid-stimulating hormone ( = 9.56 × 10) and alkaline phosphatase levels ( = 3.07 × 10). Furthermore, a higher expression of at diagnosis showed a suggestive association with the occurrence of secondary adverse events ( = 0.034). Our findings provide initial clues regarding the shared genetic factors underlying both ALL onset and prognosis. These insights may offer potential guidance for refined risk stratification and personalized survivorship care.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12935-025-04128-8.