A novel exonic rearrangement affecting MLH1 and the contiguous LRRFIP2 is a founder mutation in Portuguese Lynch syndrome families.

Abstract

PURPOSE:

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.

CONCLUSION:

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: Manuela Pinheiro, Carla Pinto, Ana Peixoto, Isabel Veiga, Bárbara Mesquita, Rui Henrique, Manuela Baptista, Maria Fragoso, Olga Sousa, Helena Pereira, Carla Marinho, Luis Moreira Dias, Manuel R Teixeira
• Journal: Genetics in medicine : official journal of the American College of Medical Genetics (Genet Med) Vol. 13 Issue 10 Pg. 895-902 (Oct 2011) ISSN: 1530-0366 [Electronic] United States
• PMID: 21785361 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Carrier Proteins
• LRRFIP2 protein, human
• MLH1 protein, human
• Nuclear Proteins
• MutL Protein Homolog 1

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Adenocarcinoma (genetics)
• Adult
• Base Sequence
• Carrier Proteins (genetics)
• Chromosome Breakpoints
• Colorectal Neoplasms, Hereditary Nonpolyposis (genetics)
• Exons
• Founder Effect
• Gene Rearrangement
• Haplotypes
• Humans
• Microsatellite Repeats
• MutL Protein Homolog 1
• Nuclear Proteins (genetics)
• Pedigree
• Phylogeny
• Polymorphism, Single Nucleotide
• Portugal