Clinical characteristics and registry-validated extended pedigrees of germline <i>TP53</i> mutation carriers in Denmark

<div><p>Introduction</p><p><i>TP53</i> mutation carrier (Li-Fraumeni Syndrome, LFS) cohort studies often suffer from lack of extensive pedigree exploration.</p><p>Methods</p><p>We performed a nation-wide exploration of <i>TP53</i> 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.</p><p>Results</p><p>We identified 30 confirmed, six obligate and 14 assumed carriers in 15 families harboring 14 different mutations, including five novel and three <i>de novo</i> 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 <i>TP53</i> mutation carriers than the 300–1,100 expected based on estimated background population frequencies.</p><p>Conclusion</p><p>Germline <i>TP53</i> 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.</p></div

Clinical characteristics and registry-validated extended pedigrees of germline <i>TP53</i> mutation carriers in Denmark - Fig 1

<p>(A) Pedigrees of three Danish families harboring germline <i>TP53</i> mutations. (B) NM_000546 isoform of the <i>TP53</i> gene protein product showing the mutations found in this study (upper track) and all published mutations from the IARC database (lower track). In the upper track, 5 novel germline mutations described in this study are expanded. In the lower track, mutations from 9 loci in the IARC database are expanded, corresponding to the 9 non-novel mutation sites described in this study. 14 IARC mutations were left out as they were either complex (13) or not classified (1). Variant colors: blue, missense, orange, nonsense, purple, splice region, red, frameshift, green, silent, grey, protein deletion.</p

Clinical and mutational data of families with 36 confirmed or <i>obligate</i> germline <i>TP53</i> mutations carriers.

<p>Clinical and mutational data of families with 36 confirmed or <i>obligate</i> germline <i>TP53</i> mutations carriers.</p

IARC database characteristics of germline <i>TP53</i> mutations observed in both IARC and in this study (families with more than 10 confirmed carriers in the IARC database are in bold).

<p>IARC database characteristics of germline <i>TP53</i> mutations observed in both IARC and in this study (families with more than 10 confirmed carriers in the IARC database are in bold).</p