Clinical Impact of Germline Multigene Sequencing in Pediatric Cohorts with a Wide Spectrum of Neoplasms.

Clinical exome or multigene panel sequencing on blood DNA, identifying pathogenic variants in predisposition genes dominated by NF1 and TP53.

Cancer predisposition syndromes account for 8.5 to 18% of childhood cancers, mostly autosomal dominant, with a 50% transmission risk to offspring. This study enrolled 886 paediatric patients with haematological and solid neoplasms from prospective and retrospective cohorts between 2018 and 2025, analysed by clinical exome or multigene panel sequencing on blood DNA. Overall, 186 pathogenic or likely pathogenic variants were identified in 176 of 886 patients (20%), the most frequently mutated genes being NF1 (n = 35) and TP53 (n = 18); of these variants, 126 (14.2% of the cohort) were causative of the paediatric neoplasm and 56 (6.3%) were heterozygous variants in DNA repair genes associated with adult-onset predisposition syndromes. Yield varied widely by tumour type, from 80% in retinoblastoma, 60% in peripheral nerve sheath tumours and 47% in phaeochromocytoma and paraganglioma, down to 12% in neuroblastoma and 4.6% in haematological malignancies.

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

The value of this cohort lies less in the overall 20% rate, already known, than in the yield hierarchy by tumour type, which offers a usable order of priority where access to germline sequencing is constrained, with haematological malignancies closing the list at 4.6%. The most uncomfortable figure is the 6.3% of adult-onset DNA repair gene variants found in children, raising questions of disclosure and parental cascade screening that the authors do not address. The lack of detail on inclusion criteria and parental confirmation, in a generalist journal, limits interpretation of the subgroup figures.

Analysis by Dr Thibaut Benquey