The abstract is read at the publisher; the summary is JClub's.
In severe congenital neutropenia (CN) and Shwachman-Diamond syndrome (SDS), clonal hematopoiesis emerges in early childhood and follows a defined mutational sequence, with TP53 VAF >0.074 in SDS linked to progression risk.
- Why it matters: Inherited neutropenia syndromes carry high cumulative risk of MDS and AML, but it is unclear which somatic mutations, combinations, allele frequencies, and timing identify patients at highest risk.
- What they did: The authors analyzed clonal hematopoiesis in 658 samples from 309 patients using error-corrected panel sequencing with longitudinal sampling, plus single-cell DNA sequencing and single-cell colony genotyping in selected cases.
- The result: CH appeared in early childhood in 37.7% of CN and 60% of SDS patients, with mutation burden stable over decades; in CN, RUNX1 and SETBP1 emerged shortly before CN-MDS/AML, while membrane-proximal CSF3R appeared only at leukemic stage, and in SDS biallelic TP53 clones expanded with dominant TP53 VAF >0.074 discriminating progressors.
The findingWhy it mattersWhat they didThe result
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