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

Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Clinical Genetics (Impact Factor: 3.93). 11/2010; 79(6):512-22. DOI: 10.1111/j.1399-0004.2010.01594.x
Source: PubMed


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

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    • "This ethnical diversity together with a high percentage of consanguineous marriages has led to a high rate of recessively inherited diseases. Three founder mutations in the MMR genes have been described among the Ashkenazi Jewish (AJ) population: c.1906G>C (p.Ala636Pro) in MSH2, as well as c.3984_3987dupGTCA and c.3959_3962delCAAG in MSH6.891011 There is limited information regarding founder mutations in other ethnic groups in the Israeli population. "
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    ABSTRACT: Heterozygous germline mutations in any of the four mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2, cause Lynch syndrome (LS), an autosomal dominant cancer predisposition syndrome conferring a high risk of colorectal, endometrial and other cancers in adulthood. Offspring of couples where both spouses have LS have a 1:4 risk of inheriting biallelic MMR gene mutations. These cause constitutional MMR deficiency (CMMRD) syndrome, a severe recessively inherited cancer syndrome with a very broad tumor spectrum including mainly hematological malignancies, brain tumors and colon cancer in childhood and adolescence. Many CMMRD children also present with café au lait spots and axillary freckling mimicking Neurofibromatosis type 1 (NF1). We describe here our experience in Israel with five CMMRD families. The clinical presentation included brain tumors at ages 2-19 years, colon cancer at ages 9-20 years, one patient with lymphoma at age 6 years and one patient with small bowel cancer at age 22 years. In children from two non-consanguineous Ashkenazi families the common Ashkenazi founder mutations were detected homozygously in one and compound heterozygously in another. In three consanguineous families of Jewish Iranian, Bedouin and Palestinian ancestries, different homozygous mutations were identified. CMMRD is a rare syndrome, but especially in areas where founder mutations for LS and consanguinity are common pediatricians should be aware of it since they are the first to encounter these children, an early diagnosis will enable tailored cancer surveillance in the entire family and a discussion regarding the options for prenatal genetic diagnosis.
    No preview · Article · Sep 2015 · Pediatric Blood & Cancer
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    ABSTRACT: The MSH2 A636P mutation is a founder mutation in Ashkenazi Jews that causes Lynch syndrome, with a prevalence of 0.4%-0.7%. Estimates of age-specific cumulative risk and lifetime risk for colorectal cancer (CRC) and endometrial cancer (EC) specific to carriers of this mutation are not available. We studied 27 families with MSH2 A636P gene mutations identified in Israel; 13 were identified via a population-based, case-control study and 14 were identified from a clinical genetics service. Age-specific cumulative risks (penetrance) and hazard ratio (HR) estimates of CRC and EC risks were calculated and compared with the general Ashkenazi population using modified segregation analysis. An ascertainment-corrected likelihood that combined population-based and clinic-based sampling provided a powerful analysis for estimating penetrance. We analyzed 74 cases of CRC (40 in the clinic series and 34 in the population-based series), diagnosed at median ages of 50 years (men) and 49 years (women) in the combined sample. The cumulative risk of CRC at age 70 was 61.62% for men (95% confidence interval [CI], 37.49%-76.45%) and 61.08% for women (95% CI, 39.39%-75.14%), with overall HRs of 31.8 (19.9-51.0) and 41.8 (27.4-64.0), respectively. There were 28 cases of EC, diagnosed at a median age of 53.0 years. The cumulative risk of EC was 55.64% (95% CI, 33.07%-70.58%) with an overall HR of 66.7 (41.7-106.7). Lifetime risks of CRC and EC in MSH2 A636P carriers are high even after adjusting for ascertainment. These estimates are valuable for patients and providers; specialized cancer screening is necessary for carriers of this mutation.
    No preview · Article · Mar 2011 · Gastroenterology
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