Diagnostic yield of cancer predisposition in a nationwide prospective childhood acute leukemia cohort.

Germline pathogenic variants (including TP53, CEBPA, DNMT3A, MSH6, PALB2, SDHA) detected by a 189-gene panel applied to WGS, complemented by trio-WGS in high-suspicion families

The utility of whole-genome sequencing (WGS) for detecting childhood leukemia predisposition remained unclear. This nationwide, prospective, population-based study included 181 children with acute leukemia and applied a three-pronged strategy: systematic phenotyping, a germline 189-gene panel derived from WGS, and tumor sequencing of positive cases; trio-WGS was performed in 11 high-suspicion families. Nine patients had a pathogenic germline alteration: six (3.3%) a leukemia predisposition syndrome (TP53, CEBPA, DNMT3A, trisomy 21) and three (1.6%) a solid tumor predisposition syndrome (MSH6, PALB2, SDHA). Trio-WGS identified one likely pathogenic de novo DNMT3A variant, six of nine diagnoses were previously unrecognized, and the findings led to tailored surveillance in 8 of 9 patients and treatment modifications in 4 of 9.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The yield is modest (9 diagnoses out of 181, about 5%), but actionable: tailored surveillance in 8 of 9 carriers and treatment modified in 4. With only nine carriers, these percentages rest on very small numbers, and trio-WGS concerned only 11 families: the study cannot tell what the whole genome adds over the panel extracted from it. The authors themselves leave open the choice between leukemia-relevant genes and a broader panel, depending on local resources and counselling capacity.

Analysis by Dr Thibaut Benquey