title: A novel exonic rearrangement affecting MLH1 and the contiguous LRRFIP2 is a founder mutation in Portuguese Lynch syndrome families.
abstract: OBJECTIVE
  Although Lynch syndrome is characterized by marked genetic heterogeneity, some specific mutations are observed at high frequency in well-defined populations or ethnic groups due to founder effects.
  
  
  METHODS
  Genomic breakpoint identification, haplotype analysis, and mutation age determination were performed in 14 unrelated patients and 95 family members presenting the same MLH1 exonic rearrangement, among a series of 84 Lynch syndrome families with germline mutations in MLH1, MSH2, or MSH6.
  
  
  RESULTS
  All 14 probands harbored an identical deletion, comprising exons 17-19 of the MLH1 gene and exons 26-29 of the LRRFIP2 gene, corresponding to the MLH1 mutation c.1896 + 280_oLRRFIP2:c.1750-678del. This mutation represents 17% of all deleterious mismatch repair mutations in our series. Haplotype analysis showed a conserved region of approximately 1 Mb, and the mutation age was estimated to be 283 ± 78 years. All 14 families are originated from the Porto district countryside.
  
  
  CONCLUSIONS
  We have identified a novel MLH1 exonic rearrangement that is a common founder mutation in Lynch syndrome families, indicating that screening for this rearrangement as a first step may be cost-effective during genetic testing of Lynch syndrome suspects of Portuguese ancestry, especially those originating from the Porto district.
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Manuela
authors.initials: M
authors.lastname: Pinheiro
authors.forename: Carla
authors.initials: C
authors.lastname: Pinto
authors.forename: Ana
authors.initials: A
authors.lastname: Peixoto
authors.forename: Isabel
authors.initials: I
authors.lastname: Veiga
authors.forename: Bárbara
authors.initials: B
authors.lastname: Mesquita
authors.forename: Rui
authors.initials: R
authors.lastname: Henrique
authors.forename: Manuela
authors.initials: M
authors.lastname: Baptista
authors.forename: Maria
authors.initials: M
authors.lastname: Fragoso
authors.forename: Olga
authors.initials: O
authors.lastname: Sousa
authors.forename: Helena
authors.initials: H
authors.lastname: Pereira
authors.forename: Carla
authors.initials: C
authors.lastname: Marinho
authors.forename: Luis
authors.initials: L
authors.lastname: Moreira Dias
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D056905:Chromosome Breakpoints; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D005091:Exons; D018703:Founder Effect; D015321:Gene Rearrangement; D006239:Haplotypes; D006801:Humans; D018895:Microsatellite Repeats; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D011174:Portugal
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C120550:LRRFIP2 protein, human; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1