Harvard Reproductive Endocrine Sciences Center, Massachusetts General Hospital, Boston, MA 02114, USA.
Sci Transl Med. 2010 May 19;2(32):32rv2. doi: 10.1126/scitranslmed.3000288.
Isolated gonadotropin-releasing hormone (GnRH) deficiency is a treatable albeit rare form of reproductive failure that has revealed physiological mechanisms controlling human reproduction, but despite substantial progress in discovering pathogenic single-gene defects, most of the genetic basis of GnRH deficiency remains uncharted. Although unbiased genetic investigations of affected families have identified mutations in previously unsuspected genes as causes of this disease in some cases, their application has been severely limited because of the negative effect of GnRH deficiency on fertility; moreover, relatively few of the many candidate genes nominated because of biological plausibility from in vitro or animal model experiments were subsequently validated in patients. With the advent of exciting technological platforms for sequencing, homozygosity mapping, and detection of structural variation at the whole-genome level, human investigations are again assuming the leading role for gene discovery. Using human GnRH deficiency as a paradigm and presenting original data from the screening of numerous candidate genes, we discuss the emerging model of patient-focused clinical genetic research and its complementarities with basic approaches in the near future.
孤立性促性腺激素释放激素（GnRH）缺乏症是一种可治疗但罕见的生殖功能障碍形式，它揭示了控制人类生殖的生理机制，但尽管在发现致病性单基因缺陷方面取得了重大进展，GnRH 缺乏症的遗传基础仍有很大一部分尚未被发现。虽然对受影响家庭进行无偏见的遗传调查已经在某些情况下确定了以前未被怀疑的基因突变是导致这种疾病的原因，但由于 GnRH 缺乏症对生育能力的负面影响，其应用受到严重限制；此外，由于体外或动物模型实验的生物学合理性而提名的许多候选基因中，只有相对较少的基因随后在患者中得到验证。随着测序、纯合子作图和全基因组水平结构变异检测等令人兴奋的技术平台的出现，人类研究再次在基因发现方面发挥主导作用。我们使用人类 GnRH 缺乏症作为范例，并展示了从众多候选基因筛选中获得的原始数据，讨论了以患者为中心的临床遗传研究的新兴模式及其与基础方法在不久的将来的互补性。
