A novel 9-base pair duplication in RET exon 8 in familial medullary thyroid carcinoma

Familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasi a type 2A syndromes are dominantly inherited diseases caused by activating germline mutations of the RET protooncogene. The majority of these patients carry a germline point mutation affecting one of five cysteine residues en coded by exon 10 (codon 609, 611, 618, or 620) or 11 (codon 634). In a few FMTC families, point mutations involving noncysteine codons in exon 13 (cod ons 768, 790, and 791), 14 (codon 804), or 15 (codon 891) have been reporte d. Hirschsprung's disease is a nonneoplastic disorder associated with RET m utations leading to a loss of function effect. Mutations are identified in 50% of the familial cases and are scattered along the gene. We now report t he study of a FMTC family with four affected members and a history of fatal neonatal intestinal obstruction in the sister of the proband. Genetic anal ysis demonstrated the absence of an usual FMTC mutation and the presence of a germline 9-bp duplication in RET exon 8 in the heterozygous state in all patients with MTC. This new mutation creates an additional cysteine residu e in the extracellular cysteine-rich domain of RET. Further studies are war ranted to confirm whether this new mutation is causing MTC only or could be associated with Hirschsprung's disease.