title: Constitutional Mismatch Repair Deficiency in Israel: High Proportion of Founder Mutations in MMR Genes and Consanguinity.
abstract: BACKGROUND
  Heterozygous germline mutations in any of the 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 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.
  
  
  METHODS
  We describe our experience in seven CMMRD families demonstrating the role and importance of founder mutations and consanguinity on its prevalence. Clinical presentations included brain tumors, colon cancer, lymphoma, and small bowel cancer.
  
  
  RESULTS
  In children from two nonconsanguineous Ashkenazi Jewish (AJ) families, the common Ashkenazi founder mutations were detected; these were homozygous in one family and compound heterozygous in the other. In four consanguineous families of various ancestries, different homozygous mutations were identified. In a nonconsanguineous Caucasus/AJ family, lack of PMS2 was demonstrated in tumor and normal tissues; however, mutations were not identified.
  
  
  CONCLUSIONS
  CMMRD is rare, 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. Early diagnosis will enable tailored cancer surveillance in the entire family and a discussion regarding prenatal genetic diagnosis.
authors.affiliation: The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.|Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Hagit N
authors.initials: HN
authors.lastname: Baris
authors.affiliation: The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel.
authors.forename: Inbal
authors.initials: I
authors.lastname: Barnes-Kedar
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Pediatric Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
authors.forename: Helen
authors.initials: H
authors.lastname: Toledano
authors.affiliation: Department of Pathology, Rabin Medical Center, Hasharon Hospital, Petach Tikva, Israel.
authors.forename: Marisa
authors.initials: M
authors.lastname: Halpern
authors.affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.|Department of Pathology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Dov
authors.initials: D
authors.lastname: Hershkovitz
authors.affiliation: Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Lossos
authors.affiliation: Department of Human Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Israela
authors.initials: I
authors.lastname: Lerer
authors.affiliation: Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Peretz
authors.affiliation: Department of Gastroenterology & Liver Disease, Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Revital
authors.initials: R
authors.lastname: Kariv
authors.affiliation: The Pediatric Gastroenterology Unit, Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Shlomi
authors.initials: S
authors.lastname: Cohen
authors.affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.|Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Half
authors.affiliation: The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel.
authors.forename: Nurit
authors.initials: N
authors.lastname: Magal
authors.affiliation: The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel.
authors.forename: Valerie
authors.initials: V
authors.lastname: Drasinover
authors.affiliation: Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Wimmer
authors.affiliation: Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Goldberg
authors.affiliation: Human Molecular Genetics, Tel Hai College, Israel.
authors.forename: Dani
authors.initials: D
authors.lastname: Bercovich
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Gastroenterology Division, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Levi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D019080:Cafe-au-Lait Spots / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D003241:Consanguinity; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D006801:Humans; D007150:Immunohistochemistry; D007557:Israel; D008223:Lymphoma / Q000235:genetics; D008297:Male; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes
keywords: Lynch syndrome; café au lait spots; consanguinity; founder mutation; germline mutations; immunohistochemistry; microsatellite instability