title: Comprehensive analysis of RET gene should be performed in patients with multiple endocrine neoplasia type 2 (MEN 2) syndrome and no apparent genotype-phenotype correlation: an appraisal of p.Y791F and p.C634Y RET mutations in five unrelated Brazilian families.
abstract: BACKGROUND
  We previously identified a four-generation family with medullary thyroid cancer (MTC) and a germline p.Y791F RET mutation whose cancer lacked a strong genotype-phenotype correlation. The entire gene coding region of the RET gene should be sequenced when genotype-phenotype discrepancies are observed in patients with multiple endocrine neoplasia type 2 (MEN 2), even if a RET hotspot mutation has been identified.
  
  
  METHODS
  A new genetic test was performed in the index case of this family with the p.Y791F RET germline mutation. The entire coding region of the RET gene was investigated by direct sequencing of PCR products. Once a mutation was identified, the target exon was sequenced in all at-risk relatives.
  
  
  RESULTS
  An additional p.C634Y germline mutation in the RET gene was identified in the reported family. The double mutation occurred in cis and segregated with the phenotype. Through the Brazilian Genetic Screening Program developed at our institution, we additionally report the combination of these two mutations (p.C634Y/p.Y791F) in the RET gene in four other unrelated families. The overall penetrance of MTC and pheochromocytoma in patients with the p.C634Y/p.Y791F mutations was 79% and 13%, respectively.
  
  
  CONCLUSIONS
  Our data emphasises that a comprehensive analysis of the RET gene may reveal multiple germline mutations in MEN 2 patients who exhibit an atypical clinical course of the disease.
authors.affiliation: Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: F O F
authors.initials: FO
authors.lastname: Valente
authors.forename: M R
authors.initials: MR
authors.lastname: Dias da Silva
authors.forename: C P
authors.initials: CP
authors.lastname: Camacho
authors.forename: I S
authors.initials: IS
authors.lastname: Kunii
authors.forename: A U
authors.initials: AU
authors.lastname: Bastos
authors.forename: C C N
authors.initials: CC
authors.lastname: da Fonseca
authors.forename: H P C
authors.initials: HP
authors.lastname: Simião
authors.forename: R
authors.initials: R
authors.lastname: Tamanaha
authors.forename: R M B
authors.initials: RM
authors.lastname: Maciel
authors.forename: J M
authors.initials: JM
authors.lastname: Cerutti
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D001938:Brazil; D002116:Calcitonin / Q000097:blood; D018276:Carcinoma, Medullary / Q000235:genetics*; D018278:Carcinoma, Neuroendocrine; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D010673:Pheochromocytoma / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: D002116:Calcitonin; D051096:Proto-Oncogene Proteins c-ret