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Int. J. Mol. Sci. 2017, 18(5), 999; doi:10.3390/ijms18050999

Incomplete Segregation of MSH6 Frameshift Variants with Phenotype of Lynch Syndrome

1
Department of Molecular Medicine and Medical Biotechnology, Federico II University Medical School, 80131 Naples, Italy
2
Endoscopy Unit, Fondazione Pascale National Institute for Study and Care of Tumors, 80131 Naples, Italy
3
General Surgery Unit—Advanced Biomedical Science Department, Federico II University Medical School, 80131 Naples, Italy
4
CEINGE-Biotecnologie Avanzate, 80145 Naples, Italy
*
Author to whom correspondence should be addressed.
Academic Editor: Peter J.K. Kuppen
Received: 3 March 2017 / Revised: 21 April 2017 / Accepted: 2 May 2017 / Published: 6 May 2017
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Abstract

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. View Full-Text
Keywords: Lynch syndrome; segregation analysis; MSH6 gene; hereditary colorectal cancer; oligogenic model Lynch syndrome; segregation analysis; MSH6 gene; hereditary colorectal cancer; oligogenic model
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MDPI and ACS Style

Liccardo, R.; De Rosa, M.; Rossi, G.B.; Carlomagno, N.; Izzo, P.; Duraturo, F. Incomplete Segregation of MSH6 Frameshift Variants with Phenotype of Lynch Syndrome. Int. J. Mol. Sci. 2017, 18, 999.

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