Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, 201 Hubin South Road, Xiamen, 361004, Fujian, China.
Dig Dis Sci. 2014 Jan;59(1):64-71. doi: 10.1007/s10620-013-2875-7. Epub 2013 Oct 24.
Peutz-Jeghers Syndrome (PJS) is an autosomal dominant disorder which predisposes to the development of various cancers. Germline mutation in the serine/threonine kinase 11 gene (STK11) is known as one of the major causes of PJS. However, a notable proportion of PJS samples do not carry any mutation in STK11, suggesting possible genetic heterogeneity in the disease and the existence of other causative variants.
In order to identify other germline variants in the coding regions of the genome that are associated with PJS, we performed exome sequencing in three Chinese individuals with PJS and identified 16 common germline variants (12 protein-coding including STK11, 4 in pre-microRNAs). We further validated protein-coding variants in six PJS individuals (three with wild-type STK11) and predicted the functional impact. As result, we found that 7 coding variants are likely to have functional impacts. Especially, we identified 2 new germline variants which are represented in all six PJS samples and are independent of STK11 mutation.
Our study provided an exomic view of PJS. The germline variants identified in our analysis may help to resolve the complex genetic background of the disease and thus lead to the discovery of novel causative variants of PJS.
Peutz-Jeghers 综合征（PJS）是一种常染色体显性遗传疾病，易导致多种癌症的发生。丝氨酸/苏氨酸激酶 11 基因（STK11）的种系突变被认为是 PJS 的主要原因之一。然而，相当一部分 PJS 样本中没有携带任何 STK11 突变，这表明该疾病存在遗传异质性，可能存在其他致病变异。
为了确定与 PJS 相关的基因组编码区中的其他种系变异，我们对 3 名 PJS 中国个体进行了外显子组测序，鉴定出 16 个常见的种系变异（包括 STK11 在内的 12 个蛋白编码变异，4 个前 microRNA 变异）。我们进一步在 6 名 PJS 个体（3 名 STK11 野生型）中验证了蛋白编码变异，并预测了其功能影响。结果发现，7 个编码变异可能具有功能影响。特别是，我们鉴定出 2 个新的种系变异，这两个变异在所有 6 个 PJS 样本中均存在，且独立于 STK11 突变。
本研究提供了 PJS 的外显子组视图。我们分析中鉴定出的种系变异可能有助于解析该疾病的复杂遗传背景，并由此发现 PJS 的新致病变异。
