Department of Surgery (Urology), University of Utah School of Medicine, Salt Lake City, UT, USA.
Andrology. 2014 May;2(3):339-50. doi: 10.1111/j.2047-2927.2014.00200.x. Epub 2014 Apr 7.
Spermatogenesis involves the aggregated action of up to 2300 genes, any of which, could, potentially, provide targets for diagnostic tests of male factor infertility. Contrary to the previously proposed common variant hypothesis for common diseases such as male infertility, genome-wide association studies and targeted gene sequencing in cohorts of infertile men have identified only a few gene polymorphisms that are associated with male infertility. Unfortunately, the search for genetic variants associated with male infertility is further hampered by the lack of viable animal models of human spermatogenesis, difficulty in robustly phenotyping infertile men and the complexity of pedigree studies in male factor infertility. In this review, we describe basic genetic principles involved in understanding the genetic basis of male infertility and examine the utility and proper clinical use of the proven genetic assays of male factor infertility, specifically Y chromosome microdeletions, chromosomal translocations, karyotype, cystic fibrosis transmembrane conductance regulator mutation analysis and sperm genetic tests. Unfortunately, these tests are only able to diagnose the cause of about 20% of male factor infertility. The remainder of the review will be devoted to examining novel tests and diagnostic tools that have the potential to explain the other 80% of male factor infertility that is currently classified as idiopathic. Those tests include epigenetic analysis of the spermatozoa and the evaluation of rare genetic variants and copy number variations in patients. Success in advancing to the implementation of such areas is not only dependent on technological advances in the laboratory, but also improved phenotyping in the clinic.
精子发生涉及多达 2300 个基因的聚合作用，其中任何一个基因都可能成为男性因素不育诊断测试的靶标。与之前提出的常见疾病（如男性不育）的常见变异假说相反，对不育男性队列进行的全基因组关联研究和靶向基因测序仅确定了少数与男性不育相关的基因多态性。不幸的是，由于缺乏可行的人类精子发生动物模型、难以对不育男性进行稳健表型分析以及男性因素不育的家系研究的复杂性，寻找与男性不育相关的遗传变异进一步受到阻碍。在这篇综述中，我们描述了理解男性不育遗传基础所涉及的基本遗传原理，并检查了已证实的男性因素不育遗传检测的效用和适当临床应用，特别是 Y 染色体微缺失、染色体易位、核型、囊性纤维化跨膜电导调节剂突变分析和精子遗传检测。不幸的是，这些测试只能诊断约 20%的男性因素不育的原因。其余部分的综述将专门研究具有潜力解释目前被归类为特发性的 80%男性因素不育的其他新测试和诊断工具。这些测试包括精子的表观遗传分析以及对患者中罕见遗传变异和拷贝数变异的评估。在这些领域取得进展不仅取决于实验室技术的进步，还取决于临床表型的改善。
