Incomplete segregation of MSH6 frameshift variants with phenotype of lynch syndrome

Raffaella Liccardo, Marina De Rosa, Giovanni Battista Rossi, Nicola Carlomagno, Paola Izzo, Francesca Duraturo

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Lynch syndrome (LS), the most frequent form of hereditary colorectal cancer, involves mutations in mismatch repair genes. The aim of this study was to identify mutations in MSH6 from 97 subjects negative for mutations in MLH1 and MSH2. By direct sequencing, we identified 27 MSH6 variants, of which, nine were novel. To verify the pathogenicity of these novel variants, we performed in silico and segregation analyses. Three novel variants were predicted by in silico analysis as damaging mutations and segregated with the disease phenotype; while a novel frameshift deletion variant that was predicted to yield a premature stop codon did not segregate with the LS phenotype in three of four cases in the family. Interestingly, another frame-shift variant identified in this study, already described in the literature, also did not segregate with the LS phenotype in one of two affected subjects in the family. In all affected subjects of both families, no mutation was detected in other MMR genes. Therefore, it is expected that within these families, other genetic factors contribute to the disease either alone or in combination with MSH6 variants. We conclude that caution should be exercised in counseling for MSH6-associated LS family members.

Original languageEnglish
Article number999
JournalInternational Journal of Molecular Sciences
Volume18
Issue number5
DOIs
Publication statusPublished - May 6 2017

Fingerprint

Hereditary Nonpolyposis Colorectal Neoplasms
phenotype
mutations
Genes
Phenotype
Mutation
Repair
genes
Computer Simulation
deletion
DNA Mismatch Repair
sequencing
Nonsense Codon
Virulence
Counseling
Colorectal Neoplasms
cancer
shift

Keywords

  • Hereditary colorectal cancer
  • Lynch syndrome
  • MSH6 gene
  • Oligogenic model
  • Segregation analysis

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Computer Science Applications
  • Spectroscopy
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Incomplete segregation of MSH6 frameshift variants with phenotype of lynch syndrome. / Liccardo, Raffaella; De Rosa, Marina; Rossi, Giovanni Battista; Carlomagno, Nicola; Izzo, Paola; Duraturo, Francesca.

In: International Journal of Molecular Sciences, Vol. 18, No. 5, 999, 06.05.2017.

Research output: Contribution to journalArticle

Liccardo, Raffaella ; De Rosa, Marina ; Rossi, Giovanni Battista ; Carlomagno, Nicola ; Izzo, Paola ; Duraturo, Francesca. / Incomplete segregation of MSH6 frameshift variants with phenotype of lynch syndrome. In: International Journal of Molecular Sciences. 2017 ; Vol. 18, No. 5.
@article{6fb70bef20144a558bc96afe0756531a,
title = "Incomplete segregation of MSH6 frameshift variants with phenotype of lynch syndrome",
abstract = "Lynch syndrome (LS), the most frequent form of hereditary colorectal cancer, involves mutations in mismatch repair genes. The aim of this study was to identify mutations in MSH6 from 97 subjects negative for mutations in MLH1 and MSH2. By direct sequencing, we identified 27 MSH6 variants, of which, nine were novel. To verify the pathogenicity of these novel variants, we performed in silico and segregation analyses. Three novel variants were predicted by in silico analysis as damaging mutations and segregated with the disease phenotype; while a novel frameshift deletion variant that was predicted to yield a premature stop codon did not segregate with the LS phenotype in three of four cases in the family. Interestingly, another frame-shift variant identified in this study, already described in the literature, also did not segregate with the LS phenotype in one of two affected subjects in the family. In all affected subjects of both families, no mutation was detected in other MMR genes. Therefore, it is expected that within these families, other genetic factors contribute to the disease either alone or in combination with MSH6 variants. We conclude that caution should be exercised in counseling for MSH6-associated LS family members.",
keywords = "Hereditary colorectal cancer, Lynch syndrome, MSH6 gene, Oligogenic model, Segregation analysis",
author = "Raffaella Liccardo and {De Rosa}, Marina and Rossi, {Giovanni Battista} and Nicola Carlomagno and Paola Izzo and Francesca Duraturo",
year = "2017",
month = "5",
day = "6",
doi = "10.3390/ijms18050999",
language = "English",
volume = "18",
journal = "International Journal of Molecular Sciences",
issn = "1661-6596",
publisher = "MDPI AG",
number = "5",

}

TY - JOUR

T1 - Incomplete segregation of MSH6 frameshift variants with phenotype of lynch syndrome

AU - Liccardo, Raffaella

AU - De Rosa, Marina

AU - Rossi, Giovanni Battista

AU - Carlomagno, Nicola

AU - Izzo, Paola

AU - Duraturo, Francesca

PY - 2017/5/6

Y1 - 2017/5/6

N2 - Lynch syndrome (LS), the most frequent form of hereditary colorectal cancer, involves mutations in mismatch repair genes. The aim of this study was to identify mutations in MSH6 from 97 subjects negative for mutations in MLH1 and MSH2. By direct sequencing, we identified 27 MSH6 variants, of which, nine were novel. To verify the pathogenicity of these novel variants, we performed in silico and segregation analyses. Three novel variants were predicted by in silico analysis as damaging mutations and segregated with the disease phenotype; while a novel frameshift deletion variant that was predicted to yield a premature stop codon did not segregate with the LS phenotype in three of four cases in the family. Interestingly, another frame-shift variant identified in this study, already described in the literature, also did not segregate with the LS phenotype in one of two affected subjects in the family. In all affected subjects of both families, no mutation was detected in other MMR genes. Therefore, it is expected that within these families, other genetic factors contribute to the disease either alone or in combination with MSH6 variants. We conclude that caution should be exercised in counseling for MSH6-associated LS family members.

AB - Lynch syndrome (LS), the most frequent form of hereditary colorectal cancer, involves mutations in mismatch repair genes. The aim of this study was to identify mutations in MSH6 from 97 subjects negative for mutations in MLH1 and MSH2. By direct sequencing, we identified 27 MSH6 variants, of which, nine were novel. To verify the pathogenicity of these novel variants, we performed in silico and segregation analyses. Three novel variants were predicted by in silico analysis as damaging mutations and segregated with the disease phenotype; while a novel frameshift deletion variant that was predicted to yield a premature stop codon did not segregate with the LS phenotype in three of four cases in the family. Interestingly, another frame-shift variant identified in this study, already described in the literature, also did not segregate with the LS phenotype in one of two affected subjects in the family. In all affected subjects of both families, no mutation was detected in other MMR genes. Therefore, it is expected that within these families, other genetic factors contribute to the disease either alone or in combination with MSH6 variants. We conclude that caution should be exercised in counseling for MSH6-associated LS family members.

KW - Hereditary colorectal cancer

KW - Lynch syndrome

KW - MSH6 gene

KW - Oligogenic model

KW - Segregation analysis

UR - http://www.scopus.com/inward/record.url?scp=85019087600&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019087600&partnerID=8YFLogxK

U2 - 10.3390/ijms18050999

DO - 10.3390/ijms18050999

M3 - Article

VL - 18

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 5

M1 - 999

ER -