定制外显子组面板揭示了PCOS患者MAPK14的新突变和RUNX2基因的新突变-动脉网

Custom exome panel revealed new mutations in MAPK14 and novel mutation in RUNX2 gene in patients with PCOS

Nature 等信源发布 2025-01-16 22:52

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Abstract

摘要

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy and is both phenotypically and genotypically heterogeneous. A large number of genetic variants have been found in different genes, so far. Based on the literature, we identified 7 genes and aimed to find new causative variants in these genes.

多囊卵巢综合征（PCOS）是最常见的内分泌病，在表型和基因型上都是异质的。到目前为止，已经在不同的基因中发现了大量的遗传变异。根据文献，我们鉴定了7个基因，旨在发现这些基因中的新致病变异。

We created a targeted PCOS panel including major genes in the steroidogenezis, WNT, MAPK, and TGFβ pathways and analyzed whole-exome sequencing results. We compared the minor allele frequency (MAF) values of different variants with our results and calculated deleterious scores of newly found variants using various web-based prediction tools and ACMG pathogenicity criteria.

我们创建了一个靶向PCOS小组，其中包括类固醇生成，WNT，MAPK和TGFβ途径中的主要基因，并分析了全外显子组测序结果。我们将不同变体的次要等位基因频率（MAF）值与我们的结果进行了比较，并使用各种基于网络的预测工具和ACMG致病性标准计算了新发现变体的有害分数。

We found a novel missense mutation (p.Thr355Ile) in the .

我们在中发现了一个新的错义突变（p.Thr355Ile）。

RUNX2

gene in one patient and heterozygous mutations in the

一名患者的基因和杂合突变

MAPK14

gene (c.306_5delT and c.*8G > T) in another patient with PCOS. Five novel pathogenic moderate (PM2) intronic variants in 4 different genes in total were introduced for the first time. We also decoded 7 genes in patients with PCOS in our cohort. Two more candidate genes (

另一名PCOS患者的基因（c.306 5delT和c。*8G> T）。首次引入了总共4个不同基因中的五个新的致病性中度（PM2）内含子变体。我们还解码了我们队列中PCOS患者的7个基因。另外两个候选基因(

MAPK14

and

和

RUNX2

) may be related to PCOS.

)可能与PCOS有关。

Introduction

简介

Polycystic ovary syndrome is the most common endocrine disorder in women of reproductive age

多囊卵巢综合征是育龄妇女最常见的内分泌疾病

. Worldwide, 4-20% of women of childbearing age are affected

在世界范围内，有4-20%的育龄妇女受到影响

. Clinical findings of PCOS include the presence of PCO morphology (PCOM), infertility, acne, ovulatory dysfunction (OD), hirsutism, insulin resistance, obesity, hyperandrogenism (HA) and dyslipidemia

PCOS的临床表现包括PCO形态（PCOM），不孕症，痤疮，排卵功能障碍（OD），多毛症，胰岛素抵抗，肥胖，高雄激素血症（HA）和血脂异常

. National Institute of Health (NIH)-1990, Rotterdam-2003 and Androgen Excess (AE)-2006 criteria are used for diagnosis of PCOS

美国国立卫生研究院（NIH）-1990年，鹿特丹-2003年和雄激素过量（AE）-2006年的标准用于诊断多囊卵巢综合征

. PCOS is studied in 4 different phenotypes as phenotypes A, B, C and D. It is known that the most common (50%) phenotype among the selected clinical populations is phenotype A (HA + OD + PCOM), which together with phenotype B (HA + OD) is also referred to as classical PCOS

PCOS在表型A，B，C和D的4种不同表型中进行了研究。众所周知，在选定的临床人群中，最常见的（50%）表型是表型A（HA++OD++PCOM），它与表型B（HA++OD）一起也被称为经典PCOS

. These phenotypes differ based on the presence or absence of hyperandrogenism, ovulatory dysfunction, and polycystic ovary morphology.

这些表型根据是否存在高雄激素血症，排卵功能障碍和多囊卵巢形态而有所不同。

Many genetic changes have been studied in PCOS. They include genes involved in ovarian and adrenal steroidogenesis (

PCOS中已经研究了许多遗传变化。它们包括与卵巢和肾上腺类固醇生成有关的基因(

配置总成

CYP11A

CYP17

CYP19

CYP21

SHBG

StAR

星形

SRD5A2

)

, in gonadotropin axis (

，在促性腺激素轴中(

ESR1

左侧

LHR

AMH

AMHR2

FSH

FSH公司

FSHR

)

, in insulin signaling (

，在胰岛素信号传导中(

INS

INS公司

INSR

IRS1

IRS2

内部收益率2

)

, and in obesity-related genes (

，以及肥胖相关基因(

FTO

MC4R

MC4R系列

)

. In recent years, especially with the development of next generation sequencing technologies, new candidate genes or their spesific variants have been found either in family-based studies or in case-control studies

近年来，特别是随着下一代测序技术的发展，在基于家庭的研究或病例对照研究中发现了新的候选基因或其特异性变异

In a study investigating the molecular changes in the egg cell microenvironment at miRNA level in PCOS patients, certain differences were detected in MAPK, insulin, Wnt and TGFβ signaling pathways

在一项研究PCOS患者卵细胞微环境miRNA水平分子变化的研究中，MAPK、胰岛素、Wnt和TGF信号通路存在一定差异

. Today, there is no certain diagnostic PCOS genetic panel currently used to detect PCOS in patients. In our previous study we identified novel

今天，目前还没有特定的PCOS诊断基因面板用于检测患者的PCOS。在我们之前的研究中，我们确定了新颖的

INSR

gene variations by employing exome sequencing in PCOS patients

PCOS患者外显子组测序的基因变异

. In the current study, we investigated the variations of genes that we hypothesized, might be important for the signaling pathways that were mentioned above where differences in miRNA levels were found in PCOS patients. We also aim to highlight variants of interest for future functional studies that may contribute to understanding the complex genetic architecture of PCOS..

在目前的研究中，我们调查了我们假设的基因变异，这些变异可能对上述在PCOS患者中发现miRNA水平差异的信号通路很重要。我们还旨在强调未来功能研究中感兴趣的变体，这些变体可能有助于理解PCOS的复杂遗传结构。。

Results

结果

We customised PCOS panel containing 7 genes in different pathways in 16 patients with phenotype A who were diagnosed according to the AE-PCOS diagnostic criteria. All patients were presenting not only hirsutism (Ferriman-Gallwey scores ≥ 8) but also had PCO morphology (the presence of ≥ 20 follicles in the ovary with a size of 2–9 mm or total ovarian volume > 10 ml, based on 2018 International Guidelines for the assessment of PCOS) with ovarain dysfunction profile.

我们定制了16例根据AE-PCOS诊断标准诊断的A型表型患者的PCOS面板，其中包含7个不同途径的基因。所有患者不仅表现出多毛症（Ferriman-Gallwey评分≥8），而且还具有PCO形态（卵巢中存在≥20个卵泡，大小为2-9毫米或总卵巢体积） > 10。

The menstrual cycle profile of all patients except one case was > 35 days..

除一例患者外，所有患者的月经周期均>35天。。

Demographic profiles of PCOS patients

多囊卵巢综合征患者的人口统计学特征

The mean age of patients was 22.3 ± 4.3 and BMI was 26.8 ± 5.5 kg/m2. The ratio of patients whose BMI that bigger than 25 (> 25 kg/m2 ) was 62.5% (

患者的平均年龄为22.3±4.3岁，BMI为26.8±5.5 kg/m2。BMI大于25（>25 kg/m2）的患者比例为62.5%(

= 10). The hormon levels of patients was following; FSH (5.6 ± 1.8 mIU/mL), LH(8.3 ± 6.3 mIU/mL), E2 (43.3 ± 28.2 pg/mL), PRL (14.3 ± 9.8 mIU/mL), TSH (1.6 ± 0.6) mIU/mL), FT4 (1.1 ± 0.2 nmol/L), total testosteron (29.4 ± 14.2 ng/mL), DHEAS (259.1 ± 110.6 µg/dL), HbA1C (5.3 ± 0.3 mmol/mol), cholesterol (169.0 ± 40.4 mg/dL), HDL (47.5 ± 10.8 mg/dL), LDL (102.2 ± 32.5 mg/dL), VLDL (18.8 ± 7.9 mg/dL) (Table .

= 10）。患者的荷尔蒙水平如下；FSH（5.6±1.8 mIU/mL），LH（8.3±6.3 mIU/mL），E2（43.3±28.2 pg/mL），PRL（14.3±9.8 mIU/mL），TSH（1.6±0.6）mIU/mL），FT4（1.1±0.2 nmol/L），总睾酮（29.4.2 ng/mL），DHEAS（259.1±110.6µg/dL），HbA1C（5.3±0.3 mmol/mol），胆固醇（169.0±40.4 mg/dL），HDL（47.5±10.8 mg/dL），LDL（102.2±32.5 mg/dL），VLDL（18.8±）7.9毫克/分升）（表。

). Among the hormones evaluated in the early phase of menstruation, the average LH/FSH ratio was 1.5 ± 1.2, while two cases (12.5%) with a ratio > 2 were detected. HOMA-IR values of the PCOS patients were 2.6 ± 1.9. The proportion of patients with HOMA-IR values exceeding 2.5, the upper threshold of the normal range, was 31.3% (5 out of 16 patients)..

)。在月经早期评估的激素中，LH/FSH的平均比率为1.5± 1.2, 而检测到两例（12.5%），比例>2。。。

Table 1 Biochemical outputs of descriptive parameters in PCOS patients.

表1 PCOS患者描述性参数的生化输出。

Full size table

全尺寸表

Among all patients, the one carrying the

在所有患者中，携带

MAPK14

mutation exhibited the highest levels of FSH, PRL, and total testosterone, alongside the lowest TSH level, suggesting a potential genotype-phenotype correlation with this mutation. Similarly, the patient with the

。同样，患有

RUNX2

mutation had the second highest HOMA-IR value, indicating a possible link between this genetic variant and insulin resistance, a common feature in PCOS (Table

突变具有第二高的HOMA-IR值，表明该遗传变异与胰岛素抵抗（PCOS的常见特征）之间可能存在联系（表

Custom exome panel results-novel candidate variants

自定义外显子组面板产生新的候选变体

We found a novel mutation in

我们发现了一个新的突变

RUNX2

(NM_001024630.4) gene and compound heterozygous mutation in

（NM\U 001024630.4）基因和复合杂合突变

MAPK14

gene (NM_139012.3) in two different patients with PCOS. The novel mutation (c.1064 C > T) was found to be located in exon 8 region of

两名不同的PCOS患者的基因（NM\U 139012.3）。发现新突变（c.1064 c > T）位于

RUNX2

gene as missense mutation (p.Thr355Ile) in patient 8 (Supplemental Fig. 1). PolyPhen2, sorting intolerant from tolerant (SIFT) and Grantham scores (Table

患者8中的基因为错义突变（p.Thr355Ile）（补充图1）。PolyPhen2，从容忍度（SIFT）和格兰瑟姆得分（表

) of this missense mutation showed different scores but we found that phyloP value of novel mutation that causing amino acid change from threonine to isoleucine at 355th position of RUNX2 protein has a value of 0.032. Based on ACMG criteria it was classified in PM1, PM2 (pathohenic moderate) level.

)。根据ACMG标准，将其分为PM1，PM2（病理性中度）水平。

Table 2 Computational prediction scores of novel mutation in

表2新突变的计算预测得分

RUNX2

gene.

基因。

Full size table

全尺寸表

On the other hand, one nucleotide deletion (c.306_5delT, a.k.a rs61763106, MAF = 0.156) in splice site region was in compound heterozygous state with c.*8G > T (a.k.a rs115711278, MAF = 0.003) which is located at 3’UTR region of

另一方面，剪接位点区域的一个核苷酸缺失（c.306 u 5delT，又称rs61763106，MAF=0.156）处于复合杂合状态，c。*8G> T（又称rs115711278，MAF=0.003）位于

MAPK14

gene in second patient (Table

第二位患者的基因（表

, Supplemental Figs. 2 and 3). Rs11511278 was classsified as VUS, while rs617336106 was scored as BA1 and BS2 according to ACMG criteria and varsome prediction tools.

，补充图2和3）。根据ACMG标准和varsome预测工具，Rs11511278被归类为VUS，而rs617336106被评为BA1和BS2。

Table 3 Nomenclature of compound heterozygous mutations in

表3中复合杂合突变的命名

MAPK14

gene.

基因。

Full size table

全尺寸表

Custom exome panel results-other variations

自定义外显子组面板结果其他变化

After filtering out the minor allele frequency (MAF), we counted a total of 302 variations in 7 genes in the user-defined PCOS panel. Fifty-eight different variations (19.2%) together with 5 novel variants have been found in these genes (Fig.

在滤除次要等位基因频率（MAF）后，我们在用户定义的PCOS面板中计算了7个基因的总共302个变异。在这些基因中发现了58个不同的变异（19.2%）和5个新的变异（图）。

, supplemental Table 2).

，补充表2）。

Fig. 1

图1

Fifty-eight different genomic variations were identified in PCOS panel.

在PCOS小组中鉴定出58种不同的基因组变异。

Full size image

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The proportion of intronic variants amounted to 60.3% out of a total of 58 different variants. Five novel intronic variants were c.2179 + 45 A > G in

在总共58个不同变体中，内含子变体的比例为60.3%。五个新的内含子变体是c.2179+ 45 A > G

PTRPC

朝鲜

gene, c.1021 + 51insG and c.1021 + 65delG in

Gene，C.1021+-51insg和C.1022+-65delg

RUNX2

gene, c.448-113insT in

基因，c.448-113insT in

MAPK14

gene, c.120-4delT in

基因c.120-4delT

MAPK1

gene (Table

基因（表

). An intron variant (rs556118862) in the

)。内含子变体（rs556118862）

PTPRC

PTPRC 的

gene that has no MAF value in the gnomAD database but has a value of 0.01% in the Estonian population and was found heterozygous in 10 of 16 PCOS patients (62.5%,

该基因在gnomAD数据库中没有MAF值，但在爱沙尼亚人群中的值为0.01%，在16名PCOS患者中有10名（62.5%，

= 10) in our cohort. rs769673108 in the

=10）在我们的队列中。rs769673108在

MAPK1

gene with a MAF value of 0.02% was found heterozygous in a PCOS patient in our study. The allele frequency of rs41270086 in the

在我们的研究中，在PCOS患者中发现MAF值为0.02%的基因是杂合的。rs41270086的等位基因频率

MAPK14

gene was higher in our PCOS cohort than in the gnomAD database (0.031 versus 0.007). Based on the mutation taster prediction, this is a polymorphism.

我们的PCOS队列中的基因高于gnomAD数据库（0.031对0.007）。根据突变品尝者的预测，这是一种多态性。

Table 4 Five novel intronic variants in custom PCOS panel.

表4定制PCOS面板中的五种新型内含子变体。

Full size table

全尺寸表

Six missense variants (10.3%) were uncovered in three genes (

在三个基因中发现了六个错义变异（10.3%）(

SRD5A2

PTPRC

PTPRC 的

and

和

RUNX2

). A new variant (p.Thr355Ile) of the 6 missense variants was found heterozygous in the

)。在6个错义变体中发现了一个新变体（p.Thr355Ile）

RUNX2

gene in a patient. The mutation causing p.Thr355Ile was calculated as a benign polymorphism with respect to the databases of mutation taster, SIFT and polyphen-2 with a phlyloP value of 0.032. The most common benign polymorphism in the

患者的基因。相对于mutation taster，SIFT和polyphen-2的数据库，导致突变的p.Thr355Ile被计算为良性多态性，phlyloP值为0.032。最常见的良性多态性

SRD5A2

gene was rs523349, which causes p.Leu59Val and was found in 15 of 16 patients (93.75%) with PCOS. A heterozygous, potentially damaging missense variant (rs41269905, p.Asp123His) in the

该基因是rs523349，可引起p.Leu59Val，在16例PCOS患者中有15例（93.75%）被发现。杂合的，可能具有破坏性的错义变体（rs41269905，p.Asp123His）

PTPRC

PTPRC 的

gene was found in a patient with a much higher MAF level than the normal population (1.5%). In

在MAF水平远高于正常人群（1.5%）的患者中发现了该基因。在

SRD5A2

gene, we found a homozygous benign frameshift mutation (rs142200057, p.Ser31fs) in 14 PCOS patients. The MAF value of this SNP was 99.9% in the gnomAD database. Another heterozygous missense variant (rs150672767, p.Val1224Ile) with a MAF value of 0.1% was found in 2 patients with PCOS in the

基因，我们在14名PCOS患者中发现了纯合的良性移码突变（rs142200057，p.Ser31fs）。在gnomAD数据库中，该SNP的MAF值为99.9%。在2例PCOS患者中发现了另一个MAF值为0.1%的杂合错义变体（rs150672767，p.Val1224Ile）

PTPRC

gene. Six synonymous variants were found in 4 genes (

基因。在4个基因中发现了6个同义变体(

PTPRC

PTPRC 的

RUNX2

FZD3

and

和

MAPK1

). Among them, the heterozygous rs17612648 (p.Pro59Pro) in the

)。其中，杂合子rs17612648（p.Pro59Pro）

PTPRC

PTPRC 的

gene had a MAF value of less than 1% which was found in one patient (6.25%) with PCOS. The ratio of 3’UTR variants was the same as that of missense and synonymous variants and was found in 3 genes (

该基因的MAF值小于1%，在一名PCOS患者（6.25%）中发现。3'UTR变异的比例与错义变异和同义变异的比例相同，在3个基因中发现(

PTPRC

PTPRC 的

SRD5A2

and

和

MAPK14

). Among them, the heterozygous insertion of (AT)8 (rs1055645201) in

)。其中，（AT）8（rs1055645201）的杂合插入

SRD5A2

gene has the lowest MAF value of 0.01% and was found in our 3 PCOS patients. rs115711278 had the second lowest MAF value of 0.29% and was found only in one patient as a compound heterozygous with a more common (MAF value is 15.6%) splice region variation (rs61763106, c.306-5delT) in the

该基因的MAF值最低，为0.01%，在我们的3名PCOS患者中发现。rs115711278的MAF值第二低，为0.29%，仅在一名患者中发现为复合杂合子，其剪接区变异更为常见（MAF值为15.6%）（rs61763106，c.306-5delT）

MAPK14

gene. As to 5’UTR variants there were only 2 variants (MAF > 5.0%); one is rs56156688 in

基因。至于5'UTR变体，只有2个变体（MAF>5.0%）；一个是rs56156688 in

MAPK14

gene and the second is rs17886698 in the

基因，第二个是rs17886698

JUNB

六月

gene.

基因。

Among the 7 genes in the custom made PCOS panel, the total number of variations in the

在定制的PCOS面板中的7个基因中

SRD5A2

gene ranked first in 16 patients (

基因在16名患者中排名第一(

= 81) (Fig.

= 81）（图。

) and the lowest number of variations was detected in the

)并且在

JUNB

gene (rs17886698,

基因（rs17886698，

= 1). On the other hand, rs2241802, the only genetic variation we found in the

另一方面，rs2241802是我们在

FZD3

gene, was found in the majority of PCOS patients (93.75%,

在大多数PCOS患者中发现了该基因（93.75%，

= 15). The total number of

= 15）。总数

MAPK1

gene variations was 26 and the most common variation in this gene was a novel intronic variation (c.120-4delT) found in 11 of 16 PCOS patients. The total number of variations in the

基因变异为26，该基因中最常见的变异是在16名PCOS患者中的11名中发现的新型内含子变异（c.120-4delT）。变化的总数

PTPRC

gene was 48. Twenty-two different variations (45.8%) together with a novel intronic variation were detected in the

基因是48。在该基因中检测到22种不同的变异（45.8%）以及一种新的内含子变异

PTPRC

PTPRC 的

gene. The position of the new variation is c.2179 + 45 A > G (Fig.

基因。新变异的位置是c.2179+ 45 A > G（图）。

). The pyhloP value for this new variation was calculated to be 0.42 using the mutation taster prediction tool.

)。使用mutation taster预测工具计算出此新变异的pyhloP值为0.42。

Fig. 2

图2

A novel intron variant in

PTPRC

gene.

基因。

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Discussion

讨论

This study was conducted to identify potential genetic variations contributing to the pathogenesis of polycystic ovary syndrome (PCOS), with a focus on key signaling pathways (steroidogenic, Wnt, TGFβ, MAPK) previously linked to PCOS pathophysiology. Given the multifactorial and complex nature of PCOS, the aim was to explore new candidate genes that could provide further insights into the genetic underpinnings of the disorder.

这项研究旨在确定导致多囊卵巢综合征（PCOS）发病机制的潜在遗传变异，重点是先前与PCOS病理生理学相关的关键信号通路（类固醇生成，Wnt，TGFβ，MAPK）。鉴于多囊卵巢综合征的多因素和复杂性，目的是探索新的候选基因，以进一步了解该疾病的遗传基础。

Through a customized exome panel, we sought to investigate potential causative variations in PCOS patients and evaluate their potential clinical relevance..

通过定制的外显子组小组，我们试图调查PCOS患者的潜在致病变异，并评估其潜在的临床相关性。。

The most striking result of our study was the identification of a novel missense mutation (p.Thr355Ile) in the

我们研究中最引人注目的结果是鉴定出一种新的错义突变（p.Thr355Ile）

RUNX2

gene, which could be a candidate for autosomal dominant PCOS. This mutation, found in one patient, has not previously been associated with PCOS. Given that RUNX2 plays a role in the Wnt signaling pathway, our finding suggests that this pathway may be implicated in PCOS pathogenesis, specifically in this phenotype.

基因，可能是常染色体显性PCOS的候选者。在一名患者中发现的这种突变以前与PCOS无关。鉴于RUNX2在Wnt信号通路中起作用，我们的发现表明该通路可能与PCOS发病机制有关，特别是在这种表型中。

However, further investigation, including segregation analysis in family members, is required to determine its pathogenicity..

但是，需要进一步调查，包括家庭成员的隔离分析，以确定其致病性。。

Additionally, the identification of a compound heterozygous mutation in the

此外，鉴定了复合杂合突变

MAPK14

gene in another patient supports the hypothesis that mutations in MAPK pathway genes may contribute to PCOS. Although the clinical significance of the identified variants (c.306_5delT and c.*8G > T) remains uncertain, these mutations may play a role in

另一名患者的基因支持MAPK途径基因突变可能导致PCOS的假设。尽管鉴定出的变体（c.306 u 5delT和c。*8G> T）的临床意义仍不确定，但这些突变可能在

MAPK14

gene expression regulation, which warrants further functional studies. This finding highlights the potential for the MAPK signaling pathway to be a target for future diagnostic or therapeutic approaches. Previous studies have implicated RUNX2 and MAPK14 in ovarian function and androgen synthesis, with RUNX2 linked to estrogen deficiency and follicular development in PCOS, while MAPK14 enhances androgen synthesis through the p38 MAPK pathway, contributing to hyperandrogenism in PCOS patients.

基因表达调控，值得进一步的功能研究。这一发现突显了MAPK信号通路成为未来诊断或治疗方法目标的潜力。先前的研究表明RUNX2和MAPK14与卵巢功能和雄激素合成有关，RUNX2与PCOS中的雌激素缺乏和卵泡发育有关，而MAPK14通过p38 MAPK途径增强雄激素合成，从而导致PCOS患者的高雄激素血症。

From a clinical perspective, the discovery of these novel mutations emphasizes the importance of genetic screening in PCOS, especially for patients with atypical or severe phenotypes. While the identification of these mutations does not immediately alter clinical practice, it opens up new avenues for personalized medicine in PCOS.

从临床角度来看，这些新突变的发现强调了PCOS基因筛查的重要性，尤其是对于非典型或严重表型的患者。虽然这些突变的鉴定不会立即改变临床实践，但它为PCOS的个性化医疗开辟了新途径。

Genetic profiling could potentially aid in tailoring treatments, particularly in cases where insulin resistance or hyperandrogenism predominates. One limitation of our study is the lack of segregation analysis due to the inability to reach family members after the February 2023 earthquake in Malatya.

基因分析可能有助于定制治疗方法，特别是在胰岛素抵抗或高雄激素血症占主导地位的情况下。我们研究的一个局限性是缺乏隔离分析，因为2023年2月马来西亚地震后无法联系到家庭成员。

Future studies should include segregation analysis to further confirm the clinical significance of the identified mutations. Additionally, a broader population-based study is needed to determine whether these variants are specific to the Turkish population or have a broader relevance. In conclusion, our study introduces novel genetic variants that may contribute to PCOS pathogenesis.

未来的研究应包括分离分析，以进一步确认已鉴定突变的临床意义。。总之，我们的研究引入了可能有助于PCOS发病机制的新型遗传变异。

The findings underscore the potential role of the .

这些发现强调了该基因的潜在作用。

RUNX2

and

和

MAPK14

genes in the development of PCOS, particularly in the context of autosomal dominant inheritance. Further research is needed to explore the functional impact of these variants and their relevance to PCOS diagnosis and treatment.

PCOS发展中的基因，特别是在常染色体显性遗传的背景下。需要进一步的研究来探索这些变体的功能影响及其与PCOS诊断和治疗的相关性。

Methods

方法

Participants

参与者

We selected 16 PCOS patients based on the AE-PCOS criteria. Informed and signed consent which is in accordance with the Declaration of Helsinki was obtained from all participants and patients who received genetic counseling. The local ethics committee (Local Ethics Committee of Yozgat Bozok University) approved this study with the number of KAEK-189_2021.02.24_07..

我们根据AE-PCOS标准选择了16名PCOS患者。所有参与者和接受遗传咨询的患者均获得了符合赫尔辛基宣言的知情同意书。当地伦理委员会（约兹加特·博佐克大学当地伦理委员会）批准了这项研究，编号为KAEK-189\U 2021.02.24\U 07。。

Biochemisrty-hormone

生化激素

For hormonal and biochemical tests (Aeroset, Abbott Laboratories, Abbott Park, IL, Immulite 2000, Siemens Medical Solutions Diagnostics, Los Angeles, CA), venous blood samples were taken in the early follicular period (day 2–3 of menstruation), and such as after 8–10 h of fasting.

对于激素和生化测试（Aeroset，Abbott Laboratories，Abbott Park，IL，Immulite 2000，Siemens Medical Solutions Diagnostics，Los Angeles，CA），在卵泡早期（月经第2-3天）以及禁食8-10小时后采集静脉血样本。

Genetics-targeted custom-made exome panel

针对遗传学的定制外显子组面板

Libraries were prepared by using ION AmpliSeqTM Custom Panel Library kit following manufacturer’s instructions. Two different pools were prepared by using 92 primer couples (Supplemental Table

。通过使用92对引物制备了两个不同的库（补充表

). After barcoding and tagging process, sequencing was employed by using Ion TorrentTM Ion S5 530 chip (Thermofisher).

)。条形码和标记过程后，使用Ion TorrentTM Ion S5 530芯片（Thermofisher）进行测序。

Within the scope of bioinformatics analysis, ‘single-end’ sequence raw data (*.fastq or UBAM) obtained from next generation sequencing platform was used. Files with bai and bam extensions were analyzed with IGV (Integrative Genome Viewer). Clinvar classifications, Polyphen and SIFT scores, UCSC common SNP lists, minor allele frequencies (85%) were used while filtering variations.

在生物信息学分析的范围内，使用了从下一代测序平台获得的“单端”序列原始数据（*fastq或UBAM）。使用IGV（Integrative Genome Viewer）分析了具有bai和bam扩展名的文件。在过滤变异时，使用了Clinvar分类，Polyphen和SIFT评分，UCSC常见SNP列表，次要等位基因频率（85%）。

We run hg19 (GRCh37, Genome Reference Consortium Human Build) when designating the chromosal localisations of candidates. Clinvar, OMIM, the Genome Aggregation Database (gnomAD v2.1.1), database of single nucleotide polymorphism (dbSNP), exome variant server and the mutation taster as in silico prediction tools.

在指定候选人的染色体定位时，我们运行hg19（GRCh37，Genome Reference Consortium Human Build）。Clinvar，OMIM，基因组聚集数据库（gnomAD v2.1.1），单核苷酸多态性数据库（dbSNP），外显子组变异服务器和突变品尝器作为计算机预测工具。

The American College of Medical Genetics and Genomics (ACMG) classification of variants by using varsome web page (.

美国医学遗传学和基因组学学院（ACMG）使用varsome网页对变体进行分类（。

https://varsome.com/

) was also employed. When filtering the intronic candidates, it was taken into account that they are 10 bp away from the exon-intron junctions. Additional filtering steps were used to obtain more information about known variations, such as increasing MAF values if necessary. The phyloP scores that measure evolutionary conservation at individual alignment nucleotides were given when required..

)也被雇用了。在筛选内含子候选物时，考虑到它们距离外显子-内含子连接处10 bp。使用其他过滤步骤来获得有关已知变化的更多信息，例如必要时增加MAF值。必要时给出了测量单个比对核苷酸进化保守性的phyloP评分。。

Data availability

数据可用性

The data of current study are involved in the article and supplementary material.

本文和补充材料涉及当前研究的数据。

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Acknowledgements

致谢

Authors are appreciated Yozgat Bozok University Scientific Research and Projects Comission for granting this current study.

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Funding

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Yozgat Bozok University Scientific Research Projects Coordination Unit supported current study (6602c-TF/21–469).

约兹加特·博佐克大学科学研究项目协调股支持了当前的研究（6602c TF/21-469）。

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Faculty of Medicine, Department of Medical Genetics, Yozgat Bozok University, Yozgat, Turkey

土耳其约兹加特约兹加特博佐克大学医学遗传学系医学院

Yunus Arikan

尤努斯阿里坎

Faculty of Medicine, Department of Obstetrics and Gynaecology, Inonü University, Malatya, Turkey

伊农大学妇产科医学院，土耳其马拉蒂亚

Taylan Onat

泰国 Onat

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YA: Conceptualization, investigation, methodology, analysis, writing-original draft TO: Investigation, analysis, material and data collection, writing-review & editing.

雅：概念化，调查，方法论，分析，撰写初稿：调查，分析，材料和数据收集，写作评论和编辑。

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Arikan, Y., Onat, T. Custom exome panel revealed new mutations in

Arikan，Y.，Onat，T。自定义外显子组小组揭示了