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Abstract：
Congenital hypogonadotropic hypogonadism (cHH)/Kallmann syndrome (KS) is a rare genetic disorder with variable penetrance and a complex inheritance pattern. Consequently, it does not always follow Mendelian laws. More recently, digenic and oligogenic transmission has been recognized in 1.5-15% of cases. We report the results of a clinical and genetic investigation of five unrelated patients with cHH/KS analyzed using a customized gene panel. Patients were diagnosed according to the clinical, hormonal, and radiological criteria of the European Consensus Statement. DNA was analyzed using next-generation sequencing with a customized panel that included 31 genes. When available, first-degree relatives of the probands were also analyzed to assess genotype-phenotype segregation. The consequences of the identified variants on gene function were evaluated by analyzing the conservation of amino acids across species and by using molecular modeling. We found one new pathogenic variant of the CHD7 gene (c.576T>A, p.Tyr1928) and three new variants of unknown significance (VUSs) in IL17RD (c.960G>A, p.Met320Ile), FGF17 (c.208G>A, p.Gly70Arg), and DUSP6 (c.434T>G, p.Leu145Arg). All were present in the heterozygous state. Previously reported heterozygous variants were also found in the PROK2 (c.163del, p.Ile55*), CHD7 (c.c.2750C>T, p.Thr917Met and c.7891C>T, p.Arg2631*), FLRT3 (c.1106C>T, p.Ala369Val), and CCDC103 (c.461A>C, p.His154Pro) genes. Molecular modeling, molecular dynamics, and conservation analyses were performed on three out of the nine variants identified in our patients, namely, FGF17 (p.Gly70Arg), DUSP6 (p.Leu145Arg), and CHD7 p.(Thr917Met). Except for DUSP6, where the L145R variant was shown to disrupt the interaction between β6 and β3, needed for extracellular signal-regulated kinase 2 (ERK2) binding and recognition, no significant changes were identified between the wild-types and mutants of the other proteins. We found a new pathogenic variant of the CHD7 gene. The molecular modeling results suggest that the VUS of the DUSP6 (c.434T>G, p.Leu145Arg) gene may play a role in the pathogenesis of cHH. However, our analysis indicates that it is unlikely that the VUSs for the IL17RD (c.960G>A, p.Met320Ile) and FGF17 (c.208G>A, p.Gly70Arg) genes are involved in the pathogenesis of cHH. Functional studies are needed to confirm this hypothesis.
摘要：
先天性低促性腺激素性性腺功能减退（cHH）/Kallmann综合征（KS）是一种罕见的遗传性疾病，具有可变的外显率和复杂的遗传模式。因此,它并不总是遵循孟德尔定律。最近,在1.5-15％的病例中已经认识到双基因和寡基因传播。我们报告了使用定制基因面板分析的五名无关cHH/KS患者的临床和遗传调查结果。患者根据临床诊断，荷尔蒙，和欧洲共识声明的放射标准。使用下一代测序与包括31个基因的定制面板分析DNA。如果可用,还分析了先证者的一级亲属,以评估基因型-表型分离.通过分析跨物种的氨基酸保守性并使用分子建模来评估所鉴定的变体对基因功能的影响。我们发现了CHD7基因的一个新的致病变体(c.576T>A，p.Tyr1928）和IL17RD中未知意义的三个新变体（VUS）（c.960G>A，p.Met320Ile)，FGF17（c.208G>A，p.Gly70Arg)，和DUSP6（c.434T>G，p.Leu145Arg).全部以杂合子状态存在。先前报道的杂合变体也在PROK2中发现（c.163del，p.Ile55*),CHD7(c.c.2750C>T，p.Thr917Met和c.7891C>T，p.Arg2631*)，FLRT3(c.1106C>T，p.Ala369Val),和CCDC103(c.461A>C，p.His154Pro)基因。分子建模,分子动力学,和保守性分析是在我们的患者中确定的九个变异中的三个进行的，即,FGF17（第Gly70Arg),DUSP6（第Leu145Arg)，和CHD7p.(Thr917Met)。除DUSP6外，L145R变体显示破坏β6和β3之间的相互作用，这是细胞外信号调节激酶2（ERK2）结合和识别所必需的，在其他蛋白质的野生型和突变体之间没有发现显著的变化。我们发现了CHD7基因的一个新的致病变体。分子建模结果表明，DUSP6的VUS（c.434T>G，p.Leu145Arg）基因可能在cHH的发病机制中起作用。然而,我们的分析表明，IL17RD的VUS不太可能(c.960G>A，p.Met320Ile）和FGF17（c.208G>A，p.Gly70Arg）基因参与cHH的发病机理。需要进行功能研究来证实这一假设。
