Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary.
Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary.
BMC Med Genomics. 2024 Apr 22;17(1):98. doi: 10.1186/s12920-024-01873-z.
Premature ovarian insuffiency (POI) is one of the main cause behind infertility. The genetic analysis of POI should be part of the clinical diagnostics, as several genes have been implicated in the genetic background of it. The aim of our study was to analyse the genetic background of POI in a Hungarian cohort.
The age of onset was between 15 and 39 years. All patients had the 46,XX karyotype and they were prescreened for the most frequent POI associated FMR1 premutation. To identify genetic alterations next-generation sequencing (NGS) of 31 genes which were previously associated to POI were carried out in 48 unrelated patients from Hungary.
Monogenic defect was identified in 16.7% (8 of 48) and a potential genetic risk factor was found in 29.2% (14 of 48) and susceptible oligogenic effect was described in 12.5% (6 of 48) of women with POI using the customized targeted panel sequencing. The genetic analysis identified 8 heterozygous damaging and 4 potentially damaging variants in POI-associated genes. Further 10 potential genetic risk factors were detected in seven genes, from which EIF2B and GALT were the most frequent. These variants were related to 15 genes: AIRE, ATM, DACH2, DAZL, EIF2B2, EIF2B4, FMR1, GALT, GDF9, HS6ST2, LHCGR, NOBOX, POLG, USP9X and XPNPEP2. In six cases, two or three coexisting damaging mutations and risk variants were identified.
POI is characterized by heterogenous phenotypic features with complex genetic background that contains increasing number of genes. Deleterious variants, which were detected in our cohort, related to gonadal development (oogenesis and folliculogenesis), meiosis and DNA repair, hormonal signaling, immune function, and metabolism which were previously associated with the POI phenotype. This is the first genetic epidemiology study targeting POI associated genes in Hungary. The frequency of variants in different POI associated genes were similar to the literature, except EIF2B and GALT. Both of these genes potential risk factor were detected which could influence the phenotype, although it is unlikely that they can be responsible for the development of the disease by themselves. Advances of sequencing technologies make it possible to aid diagnostics of POI Since individual patients show high phenotypic variance because of the complex network controlling human folliculogenesis. Comprehensive NGS screening by widening the scope to genes which were previously linked to infertility may facilitate more accurate, quicker and cheaper genetic diagnoses for POI. The investigation of patient's genotype could support clinical decision-making process and pave the way for future clinical trials and therapies.
卵巢早衰（POI）是导致不孕的主要原因之一。POI 的基因分析应作为临床诊断的一部分，因为已有多个基因与 POI 的遗传背景有关。我们的研究目的是分析匈牙利队列中 POI 的遗传背景。
发病年龄在 15 至 39 岁之间。所有患者均具有 46,XX 核型，并对最常见的与 POI 相关的 FMR1 前突变进行了预筛查。为了确定遗传改变，对来自匈牙利的 48 名无关患者进行了 31 个先前与 POI 相关的基因的下一代测序（NGS）。
使用定制的靶向panel 测序，16.7%（48 例中的 8 例）确定了单基因缺陷，29.2%（48 例中的 14 例）发现了潜在的遗传风险因素，12.5%（48 例中的 6 例）描述了易感寡基因效应。在与 POI 相关的基因中，遗传分析鉴定出 8 个杂合性有害变异和 4 个潜在的有害变异。进一步在 7 个基因中检测到 10 个潜在的遗传风险因素，其中 EIF2B 和 GALT 最为常见。这些变异与 15 个基因有关：AIRE、ATM、DACH2、DAZL、EIF2B2、EIF2B4、FMR1、GALT、GDF9、HS6ST2、LHCGR、NOBOX、POLG、USP9X 和 XPNPEP2。在 6 例中，鉴定出两个或三个共存的有害突变和风险变异。
POI 的表型特征具有异质性，遗传背景复杂，包含越来越多的基因。在我们的队列中检测到的有害变异与性腺发育（卵子发生和卵泡发生）、减数分裂和 DNA 修复、激素信号转导、免疫功能和代谢有关，这些变异先前与 POI 表型有关。这是匈牙利首次针对与 POI 相关的基因进行的遗传流行病学研究。不同与 POI 相关基因的变异频率与文献相似，除了 EIF2B 和 GALT。虽然它们不太可能单独导致疾病的发生，但它们都被检测为潜在的风险因素，可能会影响表型。测序技术的进步使得对 POI 的诊断更加准确、快速和经济。通过扩大范围到以前与不孕相关的基因，进行全面的 NGS 筛查，可能有助于更准确、更快和更经济地进行 POI 的遗传诊断。对患者基因型的研究可以支持临床决策过程，并为未来的临床试验和治疗铺平道路。
