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

Gao F, Pan X, Dodd-Eaton EB, Recio CV, Montierth MD, Bojadzieva J, Mai PL, Zelley K, Johnson VE, Braun D, Nichols KE, Garber JE, Savage SA, Strong LC, Wang W. “A pedigree-based prediction model identifies carriers of deleterious de novo mutations in families with Li-Fraumeni syndrome” Genome Research 2020 Aug;30(8):1170-1180. doi: 10.1101/gr.249599.119. Epub 2020 Aug 18. PMID: 32817165; PMCID: PMC7462073

Published

August 2020

Doi

10.1101/gr.249599.119

Abstract

De novo mutations (DNMs) are increasingly recognized as rare disease causal factors. Identifying 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 20–35 yr) provides a condition for an unbiased estimate of the DNM rate: 48% (23 DNMs vs. 25 FMs); and (3) hotspot mutation R248W was not observed in DNMs, although it was 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 novel statistical approach to systematically evaluate deleterious DNMs in inherited cancer syndromes. Our approach may serve as a foundation for future studies evaluating how new deleterious mutations can be established in the germline, such as those in TP53.

Citation

@article{gao2020pedigree,
  title={A pedigree-based prediction model identifies carriers of deleterious de novo mutations in families with Li-Fraumeni syndrome},
  author={Gao, Fan and Pan, Xuedong and Dodd-Eaton, Elissa B and Recio, Carlos Vera and Montierth, Matthew D and Bojadzieva, Jasmina and Mai, Phuong L and Zelley, Kristin and Johnson, Valen E and Braun, Danielle and others},
  journal={Genome research},
  volume={30},
  number={8},
  pages={1170--1180},
  year={2020},
  publisher={Cold Spring Harbor Lab}
}