Lynch Syndrome is an autosomal dominant cancer predisposition syndrome caused by germline pathogenic variants or epimutation in one of the DNA mismatch repair genes. De novo pathogenic variants in mismatch repair genes have been described as a rare event in Lynch Syndrome (1-5%), although the prevalence of de novo pathogenic variants in Lynch Syndrome is probably underestimated. The de novo pathogenic variant was identified in a 26-year-old woman diagnosed with an adenocarcinoma of the caecum with mismatch repair protein deficiency at immunohistochemistry and a synchronous neuroendocrine tumor of the appendix with normal expression of mismatch repair proteins. DNA testing revealed deletion of exon 6 of the MLH1 gene. It appeared to be a de novo event, as the deletion was not detected in the patient's parents. The presence of a mosaicism in the patient was excluded and haplotype analysis demonstrated the paternal origin of the chromosome harboring the deletion. The de novo deletion probably originated either from a very early postzygotic or a single prezygotic mutational event, or from a gonadal mosaicism. In conclusion, the identification of de novo pathogenic variants is crucial to allow proper genetic counseling and appropriate management of the patient's family.

中文翻译：

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林奇综合征中的新生种系致病变异：罕见事件还是冰山一角？

林奇综合征是一种常染色体显性癌症易感综合征，由 DNA 错配修复基因之一的种系致病变异或表突变引起。错配修复基因中的从头致病性变异被描述为林奇综合征中的罕见事件（1-5%），尽管林奇综合征中从头致病性变异的患病率可能被低估。该从头致病性变异是在一名 26 岁女性身上发现的，她被诊断患有盲肠腺癌，免疫组织化学显示错配修复蛋白缺乏，同时患有阑尾神经内分泌肿瘤，错配修复蛋白表达正常。DNA 测试显示 MLH1 基因的外显子 6 被删除。这似乎是一个从头事件，因为在患者的父母中没有检测到删除。排除了患者中嵌合体的存在，并且单倍型分析证明了含有缺失的染色体的父系起源。从头缺失可能源自非常早期的合子后或单个合子前突变事件，或源自性腺嵌合体。总之，新发致病变异的鉴定对于进行适当的遗传咨询和对患者家庭的适当管理至关重要。