M918V RET mutation causes familial medullary thyroid carcinoma: study of 8 affected kindreds

  1. Rui M B Maciel1,4
  1. 1Department of Medicine, Thyroid Diseases Center and Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil
  2. 2Center for Endocrinology and Metabology, Hospital Geral de Fortaleza, Fortaleza, CE, Brazil
  3. 3Department of Medicine, Universidade de Fortaleza, Fortaleza, CE, Brazil
  4. 4Fleury Medicine and Health, São Paulo, SP, Brazil
  1. Correspondence should be addressed to R M B Maciel or M R Dias-da-Silva; Email: rui.maciel{at}unifesp.br or mrdsilva{at}unifesp.br
  1. Figure 1

    Pedigree of eight apparently unrelated MTC families identified through the study. Indexes cases are identified by black arrows. Full black icons represent either affected MTC proband or relatives. The sons of F7.3 are adopted.

  2. Figure 2

    Tracking evidence for RET M918V founder effect. Physical map of South America showing the geographic position of Brazil with the localization of the surrounding physical area of Jaguaribe’s valley with its river and Apodi plateau (hatched area) at the Northeastern State of Ceará.

  3. Figure 3

    Genotype–phenotype co-segregation in RET M918V largest family. We represent family 1 with the identification of the affected MTC index case by black arrow and relatives. Full black icons represent either the affected MTC proband or relatives, and half-filled icons represent relatives affected by CCH only. Empty icons with positive (+) signaling represent patients who were tested positive for M918V without clinical evidence of MTC/CCH. Empty icons with negative (−) signaling represent patients who were tested negative for M918V. Empty icons without upper signaling represent individuals who were not submitted to RET screening. *represents the presumed pioneer immigrated to northeastern Brazil from Portugal.

  4. Figure 4

    Tracking founder effect. (A) Haplotype branching trees derived from haplotype analysis of the seven mentioned patients. Family haplotypes are indicated with the corresponding family ID numbers. The markers used are shown together with their position in the deCODE genetic map. Boxed numbers correspond to common allele in respective loci. (B) Histograms of estimated age of M918V RET mutation obtained from DMLE software. The age of mutation is given in number of generations. This histogram was obtained using growth rate of 0.4411 (25 years/generation) and the proportion of sampled chromosome of 0.015. (C) Phylogenetic tree of all families (numbered from #1 to #8) and the control group (Ct).

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