Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome

L. Raskin, F. Schwenter, M. Freytsis, M. Tischkowitz, N. Wong, G. Chong, S. A. Narod, D. A. Levine, F. Bogomolniy, M. Aronson, Stephen N Thibodeau, K. S. Hunt, G. Rennert, S. Gallinger, S. B. Gruber, W. D. Foulkes

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Founder mutations are an important cause of Lynch syndrome and facilitate genetic testing in specific ethnic populations. Two putative founder mutations in MSH6 were analyzed in 2685 colorectal cancer (CRC) cases, 337 endometrial cancer (EnCa) cases and 3310 healthy controls of Ashkenazi Jewish (AJ) descent from population-based and hospital-based case-control studies in Israel, Canada and the United States. The carriers were haplotyped and the age of the mutations was estimated. MSH6*c.3984-3987dupGTCA was found in 8/2685 CRC cases, 2/337 EnCa cases, and 1/3310 controls, consistent with a high risk of CRC (odds ratio (OR) = 9.9, 95% confidence interval (CI) = 1.2-78.9, p = 0.0079) and a very high risk of EnCa (OR = 19.6, 95%CI = 1.8-217.2, p = 0.0006). MSH6*c.3959-3962delCAAG was identified in 3/2685 CRC cases, 2/337 EnCa cases and no controls. Each mutation was observed on separate conserved haplotypes. MSH6*c.3984-3987dupGTCA and MSH6*c.3959-3962delCAAG probably arose around 585 CE and 685 CE, respectively. No carriers were identified in Sephardi Jews (450 cases and 490 controls). Truncating mutations MSH6*c.3984-3987dupGTCA and MSH6*c.3959-3962delCAAG cause Lynch syndrome and are founder mutations in Ashkenazi Jews. Together with other AJ founder mutations, they contribute substantially to the incidence of CRC and EnCa and are important tools for the early diagnosis and appropriate management of AJ Lynch syndrome patients.

Original languageEnglish (US)
Pages (from-to)512-522
Number of pages11
JournalClinical Genetics
Volume79
Issue number6
DOIs
StatePublished - Jun 2011

Fingerprint

Hereditary Nonpolyposis Colorectal Neoplasms
Endometrial Neoplasms
Mutation
Colorectal Neoplasms
Genes
Jews
Odds Ratio
Confidence Intervals
Genetic Testing
Israel
Haplotypes
Population
Canada
Case-Control Studies
Early Diagnosis
Incidence

Keywords

  • Ashkenazi Jews
  • Founder mutation
  • Lynch syndrome
  • MSH6

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Raskin, L., Schwenter, F., Freytsis, M., Tischkowitz, M., Wong, N., Chong, G., ... Foulkes, W. D. (2011). Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome. Clinical Genetics, 79(6), 512-522. https://doi.org/10.1111/j.1399-0004.2010.01594.x

Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome. / Raskin, L.; Schwenter, F.; Freytsis, M.; Tischkowitz, M.; Wong, N.; Chong, G.; Narod, S. A.; Levine, D. A.; Bogomolniy, F.; Aronson, M.; Thibodeau, Stephen N; Hunt, K. S.; Rennert, G.; Gallinger, S.; Gruber, S. B.; Foulkes, W. D.

In: Clinical Genetics, Vol. 79, No. 6, 06.2011, p. 512-522.

Research output: Contribution to journalArticle

Raskin, L, Schwenter, F, Freytsis, M, Tischkowitz, M, Wong, N, Chong, G, Narod, SA, Levine, DA, Bogomolniy, F, Aronson, M, Thibodeau, SN, Hunt, KS, Rennert, G, Gallinger, S, Gruber, SB & Foulkes, WD 2011, 'Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome', Clinical Genetics, vol. 79, no. 6, pp. 512-522. https://doi.org/10.1111/j.1399-0004.2010.01594.x
Raskin, L. ; Schwenter, F. ; Freytsis, M. ; Tischkowitz, M. ; Wong, N. ; Chong, G. ; Narod, S. A. ; Levine, D. A. ; Bogomolniy, F. ; Aronson, M. ; Thibodeau, Stephen N ; Hunt, K. S. ; Rennert, G. ; Gallinger, S. ; Gruber, S. B. ; Foulkes, W. D. / Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome. In: Clinical Genetics. 2011 ; Vol. 79, No. 6. pp. 512-522.
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