Constitutional mismatch repair deficiency (CMMRD) is caused by germline pathogenic variants in both alleles of a mismatch repair gene. Patients have an exceptionally high risk of numerous pediatric malignancies and benefit from surveillance and adjusted treatment. The diversity of its manifestation, and ambiguous genotyping results, particularly from PMS2, can complicate diagnosis and preclude timely patient management. Assessment of low‐level microsatellite instability in nonneoplastic tissues can detect CMMRD, but current techniques are laborious or of limited sensitivity. Here, we present a simple, scalable CMMRD diagnostic assay. It uses sequencing and molecular barcodes to detect low‐frequency microsatellite variants in peripheral blood leukocytes and classifies samples using variant frequencies. We tested 30 samples from 26 genetically‐confirmed CMMRD patients, and samples from 94 controls and 40 Lynch syndrome patients. All samples were correctly classified, except one from a CMMRD patient recovering from aplasia. However, additional samples from this same patient tested positive for CMMRD. The assay also confirmed CMMRD in six suspected patients. The assay is suitable for both rapid CMMRD diagnosis within clinical decision windows and scalable screening of at‐risk populations. Its deployment will improve patient care, and better define the prevalence and phenotype of this likely underreported cancer syndrome.

In childhood cancer, the frequency of cancer-associated germline variants and their inheritance patterns are not thoroughly investigated. Moreover, the identification of children carrying a genetic predisposition by clinical means remains challenging. In this single-center study, we performed trio whole-exome sequencing and comprehensive clinical evaluation of a prospectively enrolled cohort of 160 children with cancer and their parents. We identified in 11/160 patients a pathogenic germline variant predisposing to cancer and a further eleven patients carried a prioritized VUS with a strong association to the cancerogenesis of the patient. Through clinical screening, 51 patients (31.3%) were identified as suspicious for an underlying cancer predisposition syndrome (CPS), but only in ten of those patients a pathogenic variant could be identified. In contrast, one patient with a classical CPS and ten patients with prioritized VUS were classified as unremarkable in the clinical work-up. Taken together, a monogenetic causative variant was detected in 13.8% of our patients using WES. Nevertheless, the still unclarified clinical suspicious cases emphasize the need to consider other genetic mechanisms including new target genes, structural variants, or polygenic interactions not previously associated with cancer predisposition.

A considerable percentage of childhood cancers are due to cancer predisposition syndromes (CPS). The ratio of CPSs caused by inherited versus de novo germline mutations and the risk of recurrence in other children are unknown. We initiated a prospective study performing whole-exome sequencing (WES) of parent-child trios in children newly diagnosed with cancer. We initially aimed to determine the interest in and acceptance of trio WES among affected families and to systematically collect demographic, medical, and family history data to analyze whether these point to an underlying CPS. Between January 2015 and December 2016, 83 (88.3%) of 94 families participated; only 11 (11.7%) refused to participate. Five (6.0%) children presented with congenital malignancies and three (3.6%) with tumors with a high likelihood of an underlying CPS. Two (2.5%) families showed malignancies in family members < 18 years, 11 (13.8%) showed relatives < 45 years with cancer, 37 (46.3%) had a positive cancer history, and 14 (17.5%) families had > 1 relative with cancer.Conclusions: Genetic testing in pediatric oncology is of great interest to the families, and the vast majority opts for investigation into potentially underlying CPSs. Trio sequencing provides unique insights into CPS in pediatric cancers and is increasingly becoming a common approach in modern oncology, and thus, trio sequencing needs also to be integrated routinely into the practice of pediatric oncology.

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