Liccardo Raffaella, De Rosa Marina, Rossi Giovanni Battista, Carlomagno Nicola, Izzo Paola, Duraturo Francesca
Department of Molecular Medicine and Medical Biotechnology, Federico II University Medical School, 80131 Naples, Italy.
Endoscopy Unit, Fondazione Pascale National Institute for Study and Care of Tumors, 80131 Naples, Italy.
Int J Mol Sci. 2017 May 6;18(5):999. doi: 10.3390/ijms18050999.
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 from 97 subjects negative for mutations in and . By direct sequencing, we identified 27 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 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.
林奇综合征（LS）是遗传性结直肠癌最常见的形式，涉及错配修复基因的突变。本研究的目的是在97名MLH1和MSH2基因无突变的受试者中鉴定MSH6基因的突变。通过直接测序，我们鉴定出27个MSH6变体，其中9个是新的。为了验证这些新变体的致病性，我们进行了计算机模拟和家系分离分析。计算机模拟分析预测有3个新变体为有害突变，并与疾病表型共分离；而一个预计会产生提前终止密码子的新移码缺失变体在该家族的4个病例中有3个未与LS表型共分离。有趣的是，本研究中鉴定出的另一个移码变体，已在文献中有所描述，在该家族的2名受影响受试者中有1名也未与LS表型共分离。在两个家族的所有受影响受试者中，其他错配修复基因均未检测到突变。因此，可以预期在这些家族中，其他遗传因素单独或与MSH6变体共同导致该疾病。我们得出结论，在为与MSH6相关的LS家族成员提供咨询时应谨慎。
