Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects
Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects
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DOI：
10.1530/erc-16-0082
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发表时间：
2016-04-01
影响因子：
3.9
通讯作者：
Beckers, Albert
中科院分区：
文献类型：
--
作者：
Daly, Adrian F.;Yuan, Bo;Beckers, Albert
体细胞嵌合体被认为是一些遗传和基因组疾病的致病机制。X连锁肢端巨人症(XLAG)综合征是一种新近表征的儿童巨人症的基因组形式，由包括GPR101在内的亚显微染色体Xq26.3重复引起的侵袭性垂体瘤引起。我们研究了XLAG综合征患者(n=18)，以确定体细胞嵌合体是否对基因组病理生理有贡献。采用高清晰度阵列比较基因组杂交技术(HD-aCGH)对18例Xq26.3重复引起的XLAG综合征患者进行检测。我们注意到，与预期值相比，患有XLAG的男性的对数比(LR)降低，这表明存在潜在的嵌合体，而女性没有表现出这种下降。与家族性男性XLAG病例相比，散发性男性有更明显的嵌合体证据，Xq26.3重复水平在16.1%到53.8%之间。使用一种新颖的个性化断点连接特异性定量液滴数字聚合酶链式反应(DdPCR)技术复制了这些特征。我们使用一种独立的ddPCR技术，研究了在无关的肢端肥大症/巨人症患者中识别XLAG综合征的可行性，并鉴定了一名女性巨人症患者，她的GPR101拷贝数变异阈值增加，随后在HD-aCGH上被诊断为XLAG综合征。利用HD-aCGH和新的ddPCR方法的组合，我们首次证明了XLAG综合征可以由染色体Xq26.3上重复的不同程度的体细胞嵌合体引起。尽管XLAG综合征的临床特征在两性中相似，但体细胞嵌合性在男性散发性中发生，但在女性中不发生。
Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101. We studied XLAG syndrome patients (n = 18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome caused by Xq26.3 duplications were identified using high-definition array comparative genomic hybridization (HD-aCGH). We noted that males with XLAG had a decreased log2 ratio (LR) compared with expected values, suggesting potential mosaicism, whereas females showed no such decrease. Compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1 and 53.8%. These characteristics were replicated using a novel, personalized breakpoint junction-specific quantification droplet digital polymerase chain reaction (ddPCR) technique. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism, and identified one female gigantism patient who had had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes.