Novel MLH1 duplication identified in Colombian families with Lynch syndrome

Abstract

Purpose: Lynch syndrome accounts for 2-4% of all colorectal cancer, and is mainly caused by germline mutations in the DNA mismatch repair genes. Our aim was to characterize the genetic mutation responsible for Lynch syndrome in an extensive Colombian family and to study its prevalence in Antioquia. Methods: A Lynch syndrome family fulfilling Amsterdam criteria II was studied by immunohistochemistry and by multiplex ligation-dependent probe amplification (MLPA). Results were confirmed by additional independent MLPA, Southern blotting, and sequencing. Results: Index case tumor immunohistochemistry results were MLH1Ϫ, MSH2ϩ, MSH6ϩ, and PMS2Ϫ. MLPA analysis detected a duplication of exons 12 and 13 of MLH1. This mutation was confirmed and characterized precisely to span 4219 base pairs. Duplication screening in this family led to the identification of six additional carriers and 13 noncarriers. We also screened 123 early-onset independent colorectal cancer cases from the same area and identified an additional unrelated carrier. Conclusion: A novel duplication of exons 12 and 13 of the MLH1 gene was detected in two independent Lynch syndrome families from Colombia. A putative founder effect and prescreening Lynch syndrome Antioquia families for this specific mutation before thorough mismatch repair mutational screening could be suggested. Genet Med 2011:13(2):155-160.

Avoidance of pseudogene interference in the detection of 3′ deletions in PMS2

“…Duplications of PMS2 have not been reported in the literature, and there are only rare reports of duplications in the other mismatch repair genes [Alonso-Espinaco et al, 2011;BaertDesurmont et al, 2007]. However, as evidenced in our study, the redesigned MLPA kit is capable of detecting duplications, and a similarly modeled table could be generated for duplications on a case by case basis.…”

Mutation spectrum in South American Lynch syndrome families

“…The MLH1 c.545 + 3A > G and the MSH2 c.942 + 3A > T have been identified as founder mutations in Italy and in Newfoundland and were also identified in Brazilian families [3]. The MLH1 c.1039-8T_1558 + 896Tdup has been suggested to represent a founder mutation in Colombia [2,11]. Mutations that were unique and herein first reported in more than one family included the MLH1 c.1853delAinsTTCTT in Brazil, the MLH1 c.1856delG in Colombia and the MSH2 c.25252_2526delAG in Brazil (Table 2) (Figure 3).…”

“…The Spanish founder mutations MLH1 c.306 + 5G > A and c.1865 T > A and MSH2 c.2635-3 T > C; c2635-5C > T; c.2063 T > G were, however, not observed in South American Lynch syndrome families [27-30]. In Colombia, the MSH2 c.1039-8T_1558 + 896Tdup was suggested to represent a founder mutation [2,11]. The Colombian population has a mixed ancestry with a strong influence from Spanish colonists and thereby genetically differs from previously studied populations [2,6].…”

“…Families that fulfilled the Amsterdam criteria [8,9] and/or the Bethesda guidelines [10] were selected from the hereditary cancer registries at the Hospital Italiano (Buenos Aires, Argentina), the Hospital de las Fuerzas Armadas (Montevideo, Uruguay), the Clinica Los Condes (Santiago, Chile), the Barretos Cancer Hospital (Barretos, Brazil) and from two databases in Colombia and in Southeastern Brazil (Figure 1, Table 1) [2,3,5,11]. Patients were informed about their inclusion into the registries, which generally contained data on family history, age at onset and results of genetic testing.…”

“… a MLPA analysis included, b Valentin et al 2011 [3] and Rossi et al 2002 [5], c Giraldo et al 2005 [2] and Alonso-Espinaco et al 2011 [11], NA Information not available, MMR mismatch-repair genes, SD standard deviation, CRC colorectal cancer.…”