New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism
New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism
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DOI：
10.1530/eje-18-0764
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发表时间：
2019-08-01
影响因子：
5.8
通讯作者：
Gontijo Silveira, Leticia Ferreira
中科院分区：
文献类型：
--
作者：
Lima Amato, Lorena Guimaraes;Montenegro, Luciana Ribeiro;Gontijo Silveira, Leticia Ferreira
背景：先天性促性腺激素减退症（CHH）是由GnRH缺乏引起的一种罕见疾病。一些基因与CHH的发病机制有关，但大多数病例仍然没有分子诊断。新一代测序（NGS）的出现使得多个区域的基因分型同时进行，速度更快，使CHH遗传知识的扩展成为可能。目的：分析巴西CHH患者的遗传特征。设计和患者：使用包含36个CHH相关基因的面板研究了130例CHH非相关患者（91例男性，39例女性）（75例正常CHH， 55例Kallmann综合征）。结果：43例（33%）CHH患者发现潜在致病性或可能致病性变异。ANOS1、FGFR1和GNRHR是最常受影响的基因。在SOX10中发现了GNRH1基因的纯合剪接位点突变和整个编码序列的缺失。在两例可逆性正常CHH患者中发现了IGSF10基因的有害变异。值得注意的是，6.9%的患者有一个以上基因的罕见变异。在SPRY4、IL17RD、FGF17、IGSF1和FLRT3基因中也发现了罕见的变异。结论：这是一项关于CHH分子遗传学的大型研究，为这种复杂的异质遗传疾病提供了新的遗传学发现。NGS已被证明是一种快速、可靠和有效的先天性CHH分子诊断工具，并可在未来靶向临床基因检测。
Context: Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. Several genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. The advent of next-generation sequencing (NGS) has allowed the simultaneous genotyping of several regions, faster, making possible the extension of the genetic knowledge of CHH.Objective: Genetic characterization of a large cohort of Brazilian CHH patients.Design and patients: A cohort of 130 unrelated patients (91 males, 39 females) with CHH (75 normosmic CHH, 55 Kallmann syndrome) was studied using a panel containing 36 CHH-associated genes.Results: Potential pathogenic or probably pathogenic variants were identified in 43 (33%) CHH patients. The genes ANOS1, FGFR1 and GNRHR were the most frequently affected. A novel homozygous splice site mutation was identified in the GNRH1 gene and a deletion of the entire coding sequence was identified in SOX10. Deleterious variants in the IGSF10 gene were identified in two patients with reversible normosmic CHH. Notably, 6.9% of the patients had rare variants in more than one gene. Rare variants were also identified in SPRY4, IL17RD, FGF17, IGSF1 and FLRT3 genes.Conclusions: This is a large study of the molecular genetics of CHH providing new genetic findings for this complex and heterogeneous genetic condition. NGS has been shown to be a fast, reliable and effective tool in the molecular diagnosis of congenital CHH and being able to targeting clinical genetic testing in the future.