A rare RET gene exon 8 mutation is found in two Greek kindreds with familial medullary thyroid carcinoma: implications for screening

Summary Objective Familial medullary thyroid carcinoma (FMTC) is caused by germ‐line mutations in the RET proto‐oncogene. These mutations concern mainly cysteine residues in exons 10 and 11, whereas noncysteine mutations in exons 13–16 are rare. Mutations in other exons have been reported only in isolated families. In this study we have analysed the RET gene in two FMTC families negative for mutations in the above exons. Design We have analysed exons 7–19 and 21 in one index patient from each family using DNA sequencing. Patients Twenty‐eight subjects from both families were clinically assessed and subsequently molecularly analysed for the presence of RET gene mutations. Results We have found the mutation c.1597G→T (Gly533Cys) in two Greek families with FMTC. The mutation was detected in all seven MTC patients of both families as well as in 13 asymptomatic relatives in the heterozygote state, although one of the patients was also a homozygote due to consanguinity. The mutation shows a wide clinical heterogeneity, as there are carrier patients with age of diagnosis ranging from 23 to 88 years. Conclusions It is likely that this mutation causes FMTC, as no other mutation was found in the RET gene, the mutation co‐segregates with FMTC, and family members without the mutation are clinically unaffected. As the same point mutation was previously found in a large Brazilian family, it may be present in other populations as well. Therefore, exon 8 of RET should be screened in FMTC families with no identified common RET mutations.