Abstract

A genetic basis of congenital isolated hypogonadotropic hypogonadism (CHH) can be defined in almost 50% of cases, albeit not necessarily the complete genetic basis. Next-generation sequencing (NGS) techniques have led to the discovery of a great number of loci, each of which has illuminated our understanding of human gonadotropin-releasing hormone (GnRH) neurons, either in respect of their embryonic development or their neuroendocrine regulation as the “pilot light” of human reproduction. However, because each new gene linked to CHH only seems to underpin another small percentage of total patient cases, we are still far from achieving a comprehensive understanding of the genetic basis of CHH. Patients have generally not benefited from advances in genetics in respect of novel therapies. In most cases, even genetic counselling is limited by issues of apparent variability in expressivity and penetrance that are likely underpinned by oligogenicity in respect of known and unknown genes. Robust genotype–phenotype relationships can generally only be established for individuals who are homozygous, hemizygous or compound heterozygotes for the same gene of variant alleles that are predicted to be deleterious. While certain genes are purely associated with normosmic CHH (nCHH) some purely with the anosmic form (Kallmann syndrome—KS), other genes can be associated with both nCHH and KS—sometimes even within the same kindred. Even though the anticipated genetic overlap between CHH and constitutional delay in growth and puberty (CDGP) has not materialised, previously unanticipated genetic relationships have emerged, comprising conditions of combined (or multiple) pituitary hormone deficiency (CPHD), hypothalamic amenorrhea (HA) and CHARGE syndrome. In this review, we report the current evidence in relation to phenotype and genetic peculiarities regarding 60 genes whose loss-of-function variants can disrupt the central regulation of reproduction at many levels: impairing GnRH neurons migration, differentiation or activation; disrupting neuroendocrine control of GnRH secretion; preventing GnRH neuron migration or function and/or gonadotropin secretion and action.

中文翻译：

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先天性性腺功能低下性腺机能亢进症的遗传学：一种寡聚性疾病的特点和表型。

摘要

几乎有50％的病例可以确定先天性性腺功能减退性腺功能减退症（CHH）的遗传基础，尽管不一定是完整的遗传基础。下一代测序（NGS）技术导致发现了大量基因座，每个基因座都阐明了我们对人促性腺激素释放激素（GnRH）神经元的理解，无论是关于胚胎发育还是对神经内分泌的调控，如人类繁殖的“领航灯”。但是，由于与CHH相关的每个新基因似乎仅占患者总数的一小部分，因此我们对CHH的遗传基础尚缺乏全面的了解。在新疗法方面，患者通常没有从遗传学进展中受益。在多数情况下，甚至遗传咨询也受到表达和外显力表观变异性问题的限制，这些问题可能由已知和未知基因的寡聚性所支撑。通常只能为纯合子，半合子或复合杂合子的个体建立稳定的基因型与表型关系，这些个体被认为具有有害的变异等位基因相同基因。尽管某些基因与普通CHH（nCHH）纯粹相关，而某些基因仅与厌氧形式（Kallmann综合征-KS）相关，但其他基因有时甚至与同种同属。尽管尚未实现CHH与体质发育和青春期延迟（CDGP）之间预期的遗传重叠，但之前未曾预料到的遗传关系出现了，包括合并的（或多种）垂体激素缺乏症（CPHD），下丘脑闭经（HA）和CHARGE综合征。在本综述中，我们报告了有关60个基因的表型和遗传特性的当前证据，这些基因的功能丧失变异可能会在许多水平上破坏生殖的中央调节：损害GnRH神经元的迁移，分化或激活；破坏GnRH分泌的神经内分泌控制；阻止GnRH神经元迁移或功能和/或促性腺激素的分泌和作用。我们报告了有关60个基因的表型和遗传特性的最新证据，这些基因的功能丧失的变异可以在许多水平上破坏生殖的中央调节：损害GnRH神经元的迁移，分化或激活；破坏GnRH分泌的神经内分泌控制；阻止GnRH神经元迁移或功能和/或促性腺激素的分泌和作用。我们报告了有关60个基因的表型和遗传特性的最新证据，这些基因的功能丧失的变异可以在许多水平上破坏生殖的中央调节：损害GnRH神经元的迁移，分化或激活；破坏GnRH分泌的神经内分泌控制；阻止GnRH神经元迁移或功能和/或促性腺激素的分泌和作用。