Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition

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Olkinuora , A , Nieminen , T T , Mårtensson , E , Rohlin , A , Ristimäki , A , Koskenvuo , L , Lepistö , A , Swedish Extended Genetic Anal Colo , Gebre-Medhin , S , Nordling , M & Peltomäki , P 2019 , ' Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition ' , Genetics In medicine , vol. 21 , no. 8 , pp. 1868-1873 .

Title: Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition
Author: Olkinuora, Alisa; Nieminen, Taina T.; Mårtensson, Emma; Rohlin, Anna; Ristimäki, Ari; Koskenvuo, Laura; Lepistö, Anna; Swedish Extended Genetic Anal Colo; Gebre-Medhin, Samuel; Nordling, Margareta; Peltomäki, Päivi
Contributor organization: Department of Medical and Clinical Genetics
Department of Pathology
Genome-Scale Biology (GSB) Research Program
Research Programs Unit
HUS Abdominal Center
II kirurgian klinikka
Department of Surgery
Date: 2019-08
Language: eng
Number of pages: 6
Belongs to series: Genetics In medicine
ISSN: 1098-3600
Abstract: Purpose: Some 10% of familial adenomatous polyposis (FAP) and 80% of attenuated polyposis (AFAP) cases remain molecularly unexplained. We scrutinized such cases by exome-wide and targeted methods to search for novel susceptibility genes. Methods: Exome sequencing was conducted on 40 unexplained (mainly sporadic) cases with FAP or AFAP from Finland. The DNA mismatch repair (MMR) gene MLH3 (MutL Homolog 3) was pinpointed and prompted a subsequent screen of similar to 1000 Swedish patients referred to clinical panel sequencing for colon tumor susceptibility. Results: Three homozygous carriers of a truncating variant in MLH3, c.3563C>G, p.Ser1188Ter, were identified among the index cases from the Finnish series. An additional biallelic carrier of the same variant was present in the Swedish series. All four patients shared a 0.8-Mb core haplotype around MLH3, suggesting a founder variant. Colorectal polyps from variant carriers showed no instability at mono-, di-, tri-, or tetranucleotide repeats, in agreement with previous findings of a minor role of MLH3 in MMR. Multiple loci were affected by loss of heterozygosity, suggesting chromosomal instability. Conclusion: Our results show that a biallelic nonsense variant of MLH3 underlies a novel syndrome with susceptibility to classical or attenuated adenomatous polyposis and possibly extracolonic tumors, including breast cancer.
Subject: biallelic germline variant
3111 Biomedicine
1184 Genetics, developmental biology, physiology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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