OBJECTIVES Serrated polyposis syndrome (SPS) is a complex disorder with a high risk of colorectal cancer for which the germline factors remain largely unknown. Here, we combined whole-exome sequencing (WES) and linkage studies in families with multiple members affected by SPS to identify candidate genes harboring rare variants with higher penetrance effects. METHODS Thirty-nine affected subjects from 16 extended SPS families underwent WES. Genome-wide linkage analysis was performed under linear and exponential models. The contribution of rare coding variants selected to be highly pathogenic was assessed using the gene-based segregation test. RESULTS A significant linkage peak was identified on chromosome 3p25.2-p22.3 (maxSNP = rs2293787; LODlinear = 2.311, LODexp = 2.11), which logarithm of the odds (LOD) score increased after fine mapping for the same marker (maxSNP = rs2293787; LODlinear = 2.4, LODexp = 2.25). This linkage signal was replicated in 10 independent sets of random markers from this locus. To assess the contribution of rare variants predicted to be pathogenic, we performed a family-based segregation test with 11 rare variants predicted to be deleterious from 10 genes under the linkage intervals. This analysis showed significant segregation of rare variants with SPS in CAPT7, TMEM43, NGLY1, and FBLN2 genes (weighted P value > 0.007). DISCUSSION Protein network analysis suggested FBLN2 as the most plausible candidate genes for germline SPS predisposition. Etiologic rare variants implicated in disease predisposition may be identified by combining traditional linkage with WES data. This powerful approach was effective for the identification of a new candidate gene for hereditary SPS.

中文翻译：

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通过连锁分析结合全外显子组测序鉴定锯齿状息肉病综合征种系易感性的新候选基因。


目的 锯齿状息肉病综合征 (SPS) 是一种复杂的疾病，具有高结直肠癌风险，其种系因素仍知之甚少。在这里，我们结合了全外显子组测序 (WES) 和对多个成员受 SPS 影响的家庭的连锁研究，以确定含有具有较高外显率效应的罕见变异的候选基因。方法 来自 16 个 SPS 大家庭的 39 名受影响受试者接受了 WES。在线性和指数模型下进行全基因组连锁分析。使用基于基因的分离测试评估了被选择为高致病性的罕见编码变异的贡献。结果在染色体 3p25.2-p22.3 上发现了一个显着的连锁峰（maxSNP = rs2293787；LOD线性 = 2.311，LODexp = 2.11），对同一标记进行精细作图后，其对数 (LOD) 分数增加 (maxSNP = rs2293787；LOD线性 = 2.4，LODexp = 2.25）。该连锁信号在来自该基因座的 10 个独立的随机标记组中被复制。为了评估预测为致病性的罕见变异的贡献，我们对连锁区间下的 10 个基因中的 11 个预计有害的罕见变异进行了基于家族的分离测试。该分析显示 CAPT7、TMEM43、NGLY1 和 FBLN2 基因中具有 SPS 的罕见变异存在显着分离（加权 P 值 > 0.007）。讨论 蛋白质网络分析表明 FBLN2 是种系 SPS 易感性最合理的候选基因。通过将传统关联与 WES 数据相结合，可以识别与疾病易感性相关的罕见病因变异。这种强大的方法有效地鉴定了遗传性 SPS 的新候选基因。