Crivelli Louise, Bubien Virginie, Jones Natalie, Chiron Jennifer, Bonnet Françoise, Barouk-Simonet Emmanuelle, Couzigou Patrice, Sevenet Nicolas, Caux Frédéric, Longy Michel
Cancer Genetics Unit, Institut Bergonié, Bordeaux, France.
INSERM U1218, University of Bordeaux, Bordeaux, France.
Eur J Hum Genet. 2017 Sep;25(9):1087-1091. doi: 10.1038/ejhg.2017.81. Epub 2017 May 17.
Cowden syndrome (CS) is an inherited autosomal dominant disorder associated with germline pathogenic variants of the PTEN tumor suppressor gene. Its phenotypical expression is highly variable and the existence of patients with a CS suggestive phenotype without pathogenic PTEN variant may be related to genetic heterogeneity. In order to explore this hypothesis through the detection of potentially deleterious variants enabling us to identify a new candidate gene, we performed whole-exome sequencing (WES) in a series of 22 CS patients without detectable PTEN pathogenic variant using conventional methods for mutation screening. We failed to identify a novel candidate gene, but interestingly in two patients WES revealed the presence of two distinct, previously undescribed Alu insertions with the same break points in exon 5. These insertions were not found in a series of 35 breast carcinomas that showed a loss of PTEN expression without a detectable alteration of this gene. This study reveals the presence of a PTEN Alu insertion hotspot involved in CS, and suggests that undetected PTEN pathogenic variants could contribute to CS.
考登综合征（CS）是一种常染色体显性遗传疾病，与抑癌基因PTEN的种系致病性变异相关。其表型表达高度可变，具有CS提示性表型但无致病性PTEN变异的患者的存在可能与基因异质性有关。为了通过检测潜在有害变异来探索这一假设，从而使我们能够鉴定一个新的候选基因，我们对一系列22例使用常规突变筛查方法未检测到PTEN致病性变异的CS患者进行了全外显子组测序（WES）。我们未能鉴定出一个新的候选基因，但有趣的是，在两名患者中，WES显示外显子5中存在两个具有相同断点的不同的、以前未描述过的Alu插入。在一系列35例显示PTEN表达缺失但该基因未检测到改变的乳腺癌中未发现这些插入。这项研究揭示了CS中存在一个涉及PTEN的Alu插入热点，并表明未检测到的PTEN致病性变异可能与CS有关。
