Genetic diagnosis of a Chinese multiple endocrine neoplasia type 2A family through whole genome sequencing
Genetic diagnosis of a Chinese multiple endocrine neoplasia type 2A family through whole genome sequencing
复制标题
通过全基因组测序对中国多发性内分泌肿瘤2A型家系进行基因诊断
DOI：
10.1007/s12038-017-9686-5
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发表时间：
2017-06-01
影响因子：
2.9
通讯作者：
Qi, Xiao-Ping
中科院分区：
文献类型：
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作者：
Du, Zhen-Fang;Li, Peng-Fei;Qi, Xiao-Ping
大约98%的多发性内分泌瘤变2A型（MEN 2A）患者具有可识别的RET突变。对患者进行预防性或早期甲状腺全切除术或嗜铬细胞瘤/甲状旁腺切除术可以预防或治愈，并已成为标准管理。对有风险的家族成员进行RET筛查的一般策略是对最常见的受影响外显子进行测序，如果阴性，则将测序扩展到其他外显子。然而，由于相同的RET突变，不同的MEN 2A家族在疾病的临床表现和MTC的侵袭性方面往往具有显著的差异，这意味着在RET编码区之外存在其他遗传位点。全基因组测序（WGS）极大地扩展了筛选的广度，从与特定疾病相关的基因到全基因组，以及潜在地，基因组包含的关于疾病或性状的所有信息。这可能是由于疾病修饰因子的累加效应。在本研究中，我们对一个典型的中国MEN 2A先证者进行了WGS，并确定了致病性RETP. C634 R突变。我们还鉴定了RET和嗜铬细胞瘤相关基因中的几个中性变体。此外，我们还发现了一些有趣的结构变异，包括基因缺失（RSPO 1，OVCH 2和AP 3S 1等）。和融合转录物（FSIP 1-BAZ 2A等）。
Approximately 98% of patients with multiple endocrine neoplasia type 2A (MEN 2A) have an identifiableRETmutation. Prophylactic or early total thyroidectomy or pheochromocytoma/parathyroid removal in patients can be preventative or curative and has become standard management. The general strategy forRETscreening on family members at risk is to sequence the most commonly affected exons and, if negative, to extend sequencing to additional exons. However, different families with MEN 2A due to the sameRETmutation often have significant variability in the clinical exhibition of disease and aggressiveness of the MTC, which implies additional genetic loci exsit beyondRETcoding region. Whole genome sequencing (WGS) greatly expands the breadth of screening from genes associated with a particular disease to the whole genome and, potentially, all the information that the genome contains about diseases or traits. This is presumably due to additive effect of disease modifying factors. In this study, we performed WGS on a typical Chinese MEN 2A proband and identified the pathogenicRETp.C634R mutation. We also identified several neutral variants withinRETand pheochromocytoma-related genes. Moreover, we found several interesting structural variants including genetic deletions (RSPO1,OVCH2andAP3S1, etc.) and fusion transcripts (FSIP1-BAZ2A, etc.).