目的:无精子症因子(AZF)区域的拷贝数变异(CNVs)和单基因突变在46,XY核型正常的日本男性中孤立的(非综合征性)非阻塞性无精子症(NOA)的发展中起主要作用吗?分别,而其他基因的变异只扮演次要角色。
背景:性染色体异常,AZF连接的微缺失,单基因突变与分离的NOA有关。已经报道了超过160个基因作为NOA的致病/易感性/候选基因。
方法:对115例孤立的NOA和正常的46,XY核型患者进行了系统的分子分析。他在2017年至2021年期间访问了我们的医院。
方法:我们研究了115例无关的日本患者。使用序列标记的PCR和多重连接依赖性探针扩增检查AZF连接的CNV,使用全外显子组测序(WES)筛选核苷酸变体。优化的序列核关联测试(SKAT-O),使用WES数据的基于基因的关联研究,进行以鉴定基因组中的新疾病相关基因。将结果与以前的研究和我们的内部控制数据进行比较。
结果:13种AZF连接的CNVs,包括迄今未报告的gr/gr三重复和部分AZFb缺失,在63例(54.8%)中被确认。当gr/gr删除时,日本常见的多态性,被排除在数据分析之外,CNVs的总频率为23/75(30.7%)。这一频率高于日本和中国的参考数据(11.1%和14.7%,分别)。在9例(7.8%)中发现了已知的NOA致病性AZF连接的CNV。已知致病基因(DMRT1,PLK4,SYCP2,TEX11和USP26)中的罕见破坏性变异和已知精子发生相关基因中的半合子/多杂合子破坏性变异(TAF7L,在9例病例中鉴定出DNAH2和DNAH17)(总计7.8%)。一些患者在多个基因中携带罕见的破坏性变异。SKAT-O没有检测到在患者组中显著积累的罕见破坏性变异的基因。
结论:参与者的数量相对较少,每个患者的临床信息都是零碎的。此外,仅通过计算机模拟分析评估已鉴定变体的致病性.
结论:这项研究表明,超过一半的日本NOA患者中存在各种AZF连接的CNV。这些结果拓宽了AZF连接的CNVs的结构变化,这是生精失败的分子诊断应考虑的。此外,这项研究的结果强调了分离的NOA的病因异质性和可能的寡原性。
背景:这项研究得到了日本科学促进会的资助(21K19283和21H0246),日本医学研究与发展机构(22ek0109464h0003),国家儿童健康与发展中心,佳能基金会,日本内分泌学会,武田科学基金会.这项研究的结果是基于从国际生殖医学中心获得的样本和患者数据,Dokkyo医科大学Sa玉医学中心,Koshigaya,日本。作者没有利益冲突要披露。
背景:不适用。
OBJECTIVE: Do copy-number variations (CNVs) in the azoospermia factor (AZF) regions and monogenic mutations play a major role in the development of isolated (non-syndromic) non-obstructive azoospermia (NOA) in Japanese men with a normal 46, XY karyotype?
CONCLUSIONS: Deleterious CNVs in the AZF regions and damaging sequence variants in eight genes likely constitute at least 8% and approximately 8% of the genetic causes, respectively, while variants in other genes play only a minor role.
BACKGROUND: Sex chromosomal abnormalities, AZF-linked microdeletions, and monogenic mutations have been implicated in isolated NOA. More than 160 genes have been reported as causative/susceptibility/candidate genes for NOA.
METHODS: Systematic molecular analyses were conducted for 115 patients with isolated NOA and a normal 46, XY karyotype, who visited our hospital between 2017 and 2021.
METHODS: We studied 115 unrelated Japanese patients. AZF-linked CNVs were examined using sequence-tagged PCR and multiplex ligation-dependent probe amplification, and nucleotide variants were screened using whole exome sequencing (WES). An optimized sequence kernel association test (SKAT-O), a gene-based association study using WES data, was performed to identify novel disease-associated genes in the genome. The results were compared to those of previous studies and our in-house control data.
RESULTS: Thirteen types of AZF-linked CNVs, including the hitherto unreported gr/gr triplication and partial AZFb deletion, were identified in 63 (54.8%) cases. When the gr/gr deletion, a common polymorphism in Japan, was excluded from data analyses, the total frequency of CNVs was 23/75 (30.7%). This frequency is higher than that of the reference data in Japan and China (11.1% and 14.7%, respectively). Known NOA-causative AZF-linked CNVs were found in nine (7.8%) cases. Rare damaging variants in known causative genes (DMRT1, PLK4, SYCP2, TEX11, and USP26) and hemizygous/multiple-heterozygous damaging variants in known spermatogenesis-associated genes (TAF7L, DNAH2, and DNAH17) were identified in nine cases (7.8% in total). Some patients carried rare damaging variants in multiple genes. SKAT-O detected no genes whose rare damaging variants were significantly accumulated in the patient group.
CONCLUSIONS: The number of participants was relatively small, and the clinical information of each patient was fragmentary. Moreover, the pathogenicity of identified variants was assessed only by in silico analyses.
CONCLUSIONS: This study showed that various AZF-linked CNVs are present in more than half of Japanese NOA patients. These results broadened the structural variations of AZF-linked CNVs, which should be considered for the molecular diagnosis of spermatogenic failure. Furthermore, the results of this study highlight the etiological heterogeneity and possible oligogenicity of isolated NOA.
BACKGROUND: This study was supported by Grants from the Japan Society for the Promotion of Science (21K19283 and 21H0246), the Japan Agency for Medical Research and Development (22ek0109464h0003), the National Center for Child Health and Development, the Canon Foundation, the Japan Endocrine Society, and the Takeda Science Foundation. The results of this study were based on samples and patient data obtained from the International Center for Reproductive Medicine, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan. The authors have no conflicts of interest to disclose.
BACKGROUND: N/A.