Sharma Nisha, Halder Ashutosh, Kaushal Seema, Kumar Manoj, Jain Manish
Department of Reproductive Biology, All India Institute of Medical Sciences, Delhi, India.
Department of Pathology, All India Institute of Medical Sciences, Delhi, India.
Front Reprod Health. 2025 Jan 3;6:1494585. doi: 10.3389/frph.2024.1494585. eCollection 2024.
Hypospermatogenesis is a common histopathological subtype of non-obstructive azoospermia and is characterized by a decrease in the total number of germ cells within the seminiferous tubule as a result of spermatogenic failure. Determination of genetic factors before intracytoplasmic sperm injection can prevent the inheritance of these factors, as hypospermatogenesis patients gives high successful sperm retrieval rate. This study aimed to identify the structural variants associated with idiopathic hypospermatogenesis (iHS) by analyzing patient cohorts diagnosed with azoospermia using whole exome sequencing.
It is a hospital-based observational study in which patients reporting with azoospermia due to spermatogenic failure were recruited prospectively. Comprehensive clinical history, blood samples, semen analysis parameters, and reproductive endocrine evaluation reports of 51 hypospermatogenesis patients were collected. The known genetic causes were investigated using XY fluorescent hybridization and Yq microdeletion for exclusion. Whole exome sequencing was performed, and the data of 42 iHS patients was analyzed to identify single nucleotide variants associated with diagnostically important male infertility genes.
Genomic analysis of SNVs identified rare deleterious candidate variants in (c.1265C>T; p.Ser422Phe), (c.955C>T; p.Gln319Glu), (c.737G>A; p.Arg245Gln), (c.378A>C; p.Lys126Asn) and (c.2179C>A; p.Arg727Ser) genes associated with 7/42 idiopathic hypospermatogenesis patients. In silico analysis of variants shows deleterious and probably damaging effects on canonical transcripts of the genes.
This exploratory genomic analysis conducted on idiopathic hypospermatogenesis patients shows prevalence of rare deleterious candidate variants in genes associated with human male infertility. The candidate variants in idiopathic hypospermatogenesis patients are heterozygous and genotypically associated with syndromic male infertility. The symptomatic heterozygosity leading to mild spermatogenic failure resulting in hypospermatogenesis points towards a multifactorial etiology of the disease. This study justifies the importance of genetic screening of idiopathic hypospermatogenesis patients for the presence of structural variants in known human male infertility genes.
精子发生减少是非梗阻性无精子症常见的组织病理学亚型，其特征是由于生精功能衰竭，生精小管内生殖细胞总数减少。由于精子发生减少的患者精子获取成功率较高，因此在进行胞浆内单精子注射前确定遗传因素可防止这些因素的遗传。本研究旨在通过对诊断为无精子症的患者队列进行全外显子组测序，来识别与特发性精子发生减少（iHS）相关的结构变异。
这是一项基于医院的观察性研究，前瞻性招募因生精功能衰竭而出现无精子症的患者。收集了51例精子发生减少患者的全面临床病史、血液样本、精液分析参数和生殖内分泌评估报告。使用XY荧光杂交和Yq微缺失进行已知遗传病因的调查以排除相关因素。进行全外显子组测序，并分析42例iHS患者的数据，以识别与具有诊断意义的男性不育基因相关的单核苷酸变异。
对单核苷酸变异的基因组分析在与7/42例特发性精子发生减少患者相关的基因（、、、和）中鉴定出罕见的有害候选变异。对变异的计算机分析显示对这些基因的典型转录本具有有害且可能有损害的影响。
对特发性精子发生减少患者进行的这项探索性基因组分析表明，与人类男性不育相关的基因中存在罕见的有害候选变异。特发性精子发生减少患者中的候选变异是杂合的，并且在基因型上与综合征性男性不育相关。导致轻度生精功能衰竭进而导致精子发生减少的症状性杂合性表明该疾病具有多因素病因。本研究证明了对特发性精子发生减少患者进行已知人类男性不育基因结构变异遗传筛查的重要性。
