Open AccessClinical characteristics and registry-validated extended pedigrees of germline TP53 mutation carriers in Denmark
Author(s) -
Ulrik Kristoffer Stoltze,
AnneBine Skytte,
Henriette Roed,
Henrik Hasle,
Bent Ejlertsen,
Thomas van Overeem Hansen,
Kjeld Schmiegelow,
AnneMarie Gerdes,
Karin Wadt
Publication year - 2018
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0190050
Subject(s) - pedigree chart , germline mutation , germline , mutation , genetics , medicine , cancer , population , founder effect , biology , haplotype , genotype , gene , environmental health
Introduction TP53 mutation carrier (Li-Fraumeni Syndrome, LFS) cohort studies often suffer from lack of extensive pedigree exploration. Methods We performed a nation-wide exploration of TP53 mutation carrier families identified through all clinical genetics departments in Denmark. Pedigrees were expanded and verified using unique national person identification, cancer, cause of death, pathology, and church registries. Results We identified 30 confirmed, six obligate and 14 assumed carriers in 15 families harboring 14 different mutations, including five novel and three de novo germline mutations. All but two (96%) developed cancer by age 54 years [mean debut age; 29.1 y., median 33.0 y., n = 26 (17F, 9M), range 1–54 y]]. Cancer was the primary cause of all deaths [average age at death; 34.5 years]. Two tumors were identified through registry data alone. Two independent families harbored novel c.80delC mutations shown to be related through an ancestor born in 1907. This exhaustive national collection yielded markedly fewer TP53 mutation carriers than the 300–1,100 expected based on estimated background population frequencies. Conclusion Germline TP53 mutations in Denmark are likely to be drastically underdiagnosed despite their severe phenotype. Following recent advances in surveillance options of LFS patients, lack of pre-symptomatic testing may lead to the mismanagement of some individuals.