Diagnostic yield of cancer predisposition in a nationwide prospective childhood acute leukemia cohort
Abstract The utility of whole-genome sequencing (WGS) for detecting childhood leukemia predisposition remains unclear. We perform a nationwide, prospective, population-based study of 181 children with acute leukemia to assess diagnostic yield and clinical utility of a uniformly applied three-pronged strategy, including systematic phenotyping, germline WGS-based 189-gene panel and tumor sequencing of positive cases. Trio-WGS is performed in 11 high-suspicion families. Nine patients have pathogenic germline alterations: six (3.3%) with leukemia predisposition syndromes ( TP53, CEBPA, DNMT3A , trisomy 21) and three (1.6%) with solid tumor predisposition syndromes ( MSH6, PALB2, SDHA ). Trio-WGS identifies one likely-pathogenic de novo DNMT3A variant. Six of nine diagnoses are previously unrecognized. Findings lead to tailored surveillance in 8/9 patients and treatment modifications in 4/9. Here, we show that this strategy gives a modest diagnostic yield. Nevertheless, the actionability of the findings supports its feasibility and validity in practice. Whether to restrict analysis to leukemia-relevant genes or broaden the panel should reflect local resources and counseling capacity.
Authors
- Joakim Klar (ORCID: https://orcid.org/0000-0003-4185-7409)
- Pär Gideonsson
- Bianca Tesi (ORCID: https://orcid.org/0000-0002-8253-2507)
- Linda Arvidsson
- Fulya Taylan (ORCID: https://orcid.org/0000-0002-2907-0235)
- Katja Ekholm (ORCID: https://orcid.org/0009-0005-8231-8876)
- Richard Rosenquist (ORCID: https://orcid.org/0000-0002-0211-8788)
- David Gisselsson (ORCID: https://orcid.org/0000-0002-0301-426X)
- Josefine Palle (ORCID: https://orcid.org/0000-0001-7431-2865)
- Anna Poluha (ORCID: https://orcid.org/0000-0002-4716-9423)
- Johanna Sandgren (ORCID: https://orcid.org/0000-0001-6776-2649)
- Sofie Ivarsson (ORCID: https://orcid.org/0009-0000-7099-7588)
- Carolina Maya‐González (ORCID: https://orcid.org/0000-0003-0385-475X)
- Frida Abel (ORCID: https://orcid.org/0000-0001-6958-4487)
- Ekaterina Kuchinskaya (ORCID: https://orcid.org/0009-0009-3347-6658)
- Ulrika Norén‐Nyström (ORCID: https://orcid.org/0000-0001-5606-5442)
- Tatjana Pandzic (ORCID: https://orcid.org/0009-0006-9032-4616)
- Lars Palmqvist (ORCID: https://orcid.org/0000-0001-9274-360X)
- Kristina Lagerstedt‐Robinson (ORCID: https://orcid.org/0000-0001-9848-0468)
- Jonas Abrahamsson (ORCID: https://orcid.org/0000-0002-9240-3522)
- Ann Nordgren (ORCID: https://orcid.org/0000-0003-3285-4281)
- Maria Hellberg (ORCID: https://orcid.org/0009-0009-2699-4270)
- Gisela Barbany (ORCID: https://orcid.org/0000-0003-3185-2962)
- Hartmut Vogt (ORCID: https://orcid.org/0000-0001-6009-7789)
- Pernilla Grillner (ORCID: https://orcid.org/0000-0001-7570-8191)
- Sara Orrsjö (ORCID: https://orcid.org/0009-0008-9223-3923)
- Karin Belander Strålin (ORCID: https://orcid.org/0000-0002-8190-513X)
- Valtteri Wirta (ORCID: https://orcid.org/0000-0003-3811-5439)
- Emma Tham
- Paivi Lahteenmaki
- Gustaf Ljungman (ORCID: https://orcid.org/0000-0002-4949-2494)
- Britt-Marie Anderlid
- Anna Staffas
- Arja Harila
- Marie-Louise Bondeson
- Cornelis Jan Pronk
- Ninni Mu
- Irina Golovleva
Institutions
- Linköping University (SE)
- Uppsala University (SE)
- Karolinska University Hospital (SE)
- Uppsala University Hospital (SE)
- Lund University (SE)
- Science for Life Laboratory (SE)
- Sahlgrenska University Hospital (SE)
- Karolinska Institutet (SE)
- Region Västra Götaland (SE)
- Skåne University Hospital (SE)
- Linköping University Hospital (SE)
- Region Östergötland
- KTH Royal Institute of Technology (SE)
- University of Gothenburg (SE)
- Umeå University (SE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-09-28
- DOI
- https://doi.org/10.1038/s41467-026-78170-z
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00