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A Novel 9-Base Pair Duplication in RET Exon 8 in Familial Medullary Thyroid Carcinoma¹

Laboratoire de Biochimie-Secteur commun de Biologie Moléculaire de l’Hôpital Huriez (P.P., M.C., M.P.B., J.P.K., N.P.), Service d’Endocrinologie & Médecine Interne (C.B., J.L.W.), Service d’Anatomie Pathologique A (M.L.H.), Centre Hospitalier Régional Universitaire, 59037 Lille Cedex; Laboratoire de Génétique Moléculaire, Hôpital Edouard Herriot (S.G., A.C.), F-69437 Lyon Cedex; and Service d’Endocrinologie, Hôpital de Rangueil, Centre Hospitalier Universitaire (P.C.), F-31403 Toulouse Cedex 4, France

Address all correspondence and requests for reprints to: Pascal Pigny, Pharm.D., Ph.D., Laboratoire de Biochimie, Bâtiment USN-A, Clinique Marc Linquette, Centre Hospitalier Régionale Universitaire, F-59037 Lille Cedex, France. E-mail: p-pigny{at}chru-lille.fr

Familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia 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 encoded 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 (codons 768, 790, and 791), 14 (codon 804), or 15 (codon 891) have been reported. Hirschsprung’s disease is a nonneoplastic disorder associated with RET mutations 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 the study of a FMTC family with four affected members and a history of fatal neonatal intestinal obstruction in the sister of the proband. Genetic analysis 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 residue in the extracellular cysteine-rich domain of RET. Further studies are warranted to confirm whether this new mutation is causing MTC only or could be associated with Hirschsprung’s disease.

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