Pathogenic variants of DYNC2H1, KIAA0556, and PTPN11 associated with hypothalamic hamartoma
Pathogenic variants of DYNC2H1, KIAA0556, and PTPN11 associated with hypothalamic hamartoma
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DOI：
10.1212/wnl.0000000000007774
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发表时间：
2019-07-16
期刊：
影响因子：
9.9
通讯作者：
Matsumoto, Naomichi
中科院分区：
文献类型：
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作者：
Fujita, Atsushi;Higashijima, Takefumi;Matsumoto, Naomichi
我们对38例下丘脑错构瘤（HH）患者进行了深入的遗传分析，以揭示其分子生物学特征。我们使用从血液白细胞或HH样本中提取的DNA，通过全外显子组测序、基于靶捕获的深度测序或单核苷酸多态性（SNP）阵列对HH患者进行了研究。和PTPN 11的2种体细胞变体，其形成RAS/促分裂原活化蛋白激酶（MAPK）途径的一部分，以及与HH相关的已知基因的变体。SNP阵列鉴定出（3例患者中）一个位于6p22.3-p21.31的生殖细胞拷贝中性杂合性丢失（cnLOH）和2个体细胞cnLOH;一个位于11q12.2-q25，包括编码纤毛运动蛋白的DYNC 2 H1，另一个位于17p13.3-p11.2。在1例患者中证实了DYNC 2 H1的种系杂合变异体和由11q12.2-q25处的cnLOH引起的相同体细胞变异体（因此，其HH组织含有DYNC 2 H1的双等位基因变异体）。此外，在另一名患者中检测到种系和体细胞DYNC 2 H1变体的组合。结论总体而言，我们的队列在34%（13/38）的HH患者中发现了种系/体细胞变异。与纤毛相关的Shh信号通路或RAS/MAPK通路的破坏可能导致HH的发展。
ObjectiveIntensive genetic analysis was performed to reveal comprehensive molecular insights into hypothalamic hamartoma (HH).MethodsThirty-eight individuals with HH were investigated by whole exome sequencing, target capture-based deep sequencing, or single nucleotide polymorphism (SNP) array using DNA extracted from blood leukocytes or HH samples.ResultsWe identified a germline variant of KIAA0556, which encodes a ciliary protein, and 2 somatic variants of PTPN11, which forms part of the RAS/mitogen-activated protein kinase (MAPK) pathway, as well as variants in known genes associated with HH. An SNP array identified (among 3 patients) one germline copy-neutral loss of heterozygosity (cnLOH) at 6p22.3-p21.31 and 2 somatic cnLOH; one at 11q12.2-q25 that included DYNC2H1, which encodes a ciliary motor protein, and the other at 17p13.3-p11.2. A germline heterozygous variant and an identical somatic variant of DYNC2H1 arising from cnLOH at 11q12.2-q25 were confirmed in one patient (whose HH tissue, therefore, contains biallelic variants of DYNC2H1). Furthermore, a combination of a germline and a somatic DYNC2H1 variant was detected in another patient.ConclusionsOverall, our cohort identified germline/somatic alterations in 34% (13/38) of patients with HH. Disruption of the Shh signaling pathway associated with cilia or the RAS/MAPK pathway may lead to the development of HH.