A pedigree-based prediction model identifies carriers of deleterious de novo mutations in families with Li-Fraumeni syndrome

De novo mutations (DNMs) are being increasingly recognized as causal factors for rare diseases. Identifying rare DNM carriers will allow researchers to study the likely distinct molecular mechanisms of DNMs. We developed Famdenovo to predict DNM status (DNM or familial mutation, FM) of deleterious autosomal dominant germline mutations for any syndrome. We introduce Famdenovo.TP53 for Li-Fraumeni syndrome (LFS) and analyze 324 LFS family pedigrees from four US cohorts: a validation set of 186 pedigrees and a discovery set of 138 pedigrees. The concordance index for Famdenovo.TP53 prediction was 0.95 (95% CI: [0.92, 0.98]). Forty individuals (95% CI: [30, 50]) were predicted as DNM carriers, increasing the total number from 42 to 82. We compared clinical and biological features of FM versus DNM carriers: 1) cancer and mutation spectra along with parental ages were similarly distributed; 2) ascertainment criteria like early-onset breast cancer (age 20 to 35 years) provides a condition for an unbiased estimate of the DNM rate: 48% (23 DNMs vs. 25 FMs); 3) Hotspot mutation R248W was not observed in DNMs, although it is as prevalent as hotspot mutation R248Q in FMs. Furthermore, we introduce Famdenovo.brca for hereditary breast and ovarian cancer syndrome, and apply it to a small set of family data from the Cancer Genetics Network. In summary, we introduce a new study design to systematically evaluate deleterious DNMs in inherited cancer syndromes. Our findings will facilitate future studies on how new deleterious mutations are established in the germline and how rare genetic diseases prevail.