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Summary

Objective  No comprehensive information exists nationwide about the familial prevalence and age of rearranged during transfection (RET) germline mutations. The current investigation was undertaken to provide such natural history data which are urgently needed to enable factual decision-making about DNA-based screening programmes for RET germline mutations.

Design  Descriptive study drawn on countrywide referrals to a specialist surgical centre.

Patients  Included were 452 patients from 141 German RET families: 277 carriers referred for pre-emptive or therapeutic surgery, and 175 additional carriers or relatives with endocrine tumours associated with multiple endocrine neoplasia type 2 (MEN2).

Measurements  Key variables included familial prevalence, phenotype and latest year of birth of RET germline mutations.

Results  A total of 26 different RET germline mutations were identified among the 141 RET families: C634R (21%); M918T (15%); C634Y (9%); L790F/TTG[RIGHTWARDS ARROW]TTT (8%), Y791F (7%), V804M (6%); C620R and C634F (5% each); L790F/TTG[RIGHTWARDS ARROW]TTC and C634S/TGC[RIGHTWARDS ARROW]TCC (4% each); C618S/TGC[RIGHTWARDS ARROW]AGC, C634G and S891A (2% each); C618F and E768D (1% each); and in < 1% each: C609G, C611F, C611Y, C618G, C618Y, C620S/TGC[RIGHTWARDS ARROW]AGC, C620S/TGC[RIGHTWARDS ARROW]TCC, C620Y, C630R, D631Y and V804L. Most of these differences in prevalence rates, seemingly, were caused by recent spontaneous mutations in the germline. With rare exceptions, longstanding transmission was noted in at least one RET family per affected codon. Many germline mutations were traceable back to the early 20th, and a few even to the 19th century.

Conclusions  These data reveal the potential of DNA-based screening of all relevant RET exons, especially for index patients with solitary, seemingly sporadic disease.