Advanced

Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition

Olkinuora, Alisa ; Nieminen, Taina T. ; Mårtensson, Emma LU ; Rohlin, Anna LU ; Ristimäki, Ari ; Koskenvuo, Laura ; Lepistö, Anna ; Gebre-Medhin, Samuel LU ; Nordling, Margareta and Peltomäki, Päivi (2019) In Genetics in Medicine 21(8). p.1868-1873
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 ~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... (More)

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 ~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.

(Less)
Please use this url to cite or link to this publication:
author
author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
biallelic germline variant, MLH3, polyposis
in
Genetics in Medicine
volume
21
issue
8
pages
1868 - 1873
publisher
Lippincott Williams & Wilkins
external identifiers
  • scopus:85058847175
  • pmid:30573798
ISSN
1098-3600
DOI
10.1038/s41436-018-0405-x
language
English
LU publication?
yes
id
0cf75b50-8d5b-45b2-8f25-b93adf228254
date added to LUP
2019-01-14 10:41:30
date last changed
2020-07-08 04:38:35
@article{0cf75b50-8d5b-45b2-8f25-b93adf228254,
  abstract     = {<p>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 ~1000 Swedish patients referred to clinical panel sequencing for colon tumor susceptibility. Results: Three homozygous carriers of a truncating variant in MLH3, c.3563C&gt;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.</p>},
  author       = {Olkinuora, Alisa and Nieminen, Taina T. and Mårtensson, Emma and Rohlin, Anna and Ristimäki, Ari and Koskenvuo, Laura and Lepistö, Anna and Gebre-Medhin, Samuel and Nordling, Margareta and Peltomäki, Päivi},
  issn         = {1098-3600},
  language     = {eng},
  number       = {8},
  pages        = {1868--1873},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {Genetics in Medicine},
  title        = {Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition},
  url          = {http://dx.doi.org/10.1038/s41436-018-0405-x},
  doi          = {10.1038/s41436-018-0405-x},
  volume       = {21},
  year         = {2019},
}