Clinical Characteristics, Cytogenetic and Molecular Findings in Patients with Disorders of Sex Development

The clinical characteristics of patients with disorders of sex development（DSD）, and the diagnostic values of classic cytogenetic and molecular genetic assays for DSD were investigated. In the enrolled 56 cases, there were 9 cases of 46,XY DSD, 6 cases of Turner syndrome（TS）, one case of Super female syndrome, 25 cases of Klinefelter syndrome, 14 cases of 46,XX DSD, and one case of autosomal balanced rearrangements with hypospadias. The diagnosis of sex was made through physical examination, cytogenetic assay, ultrasonography, gonadal biopsy and hormonal analysis. PCR was used to detect SRY, ZFX, ZFY, DYZ3 and DYZ1 loci on Y and X chromosomes respectively. The DSD patients with the same category had similar clinical characteristics. The karyotypes in peripheral blood lymphocytes of all patients were identified. PCR-based analysis showed presence or absence of the X/Y-linked loci in several cases. Of the 9 cases of 46,XY DSD, 6 were positive for SRY, 9 for ZFX/ZFY, 9 for DYZ3 and 8 for DYZ1 loci. Of the 6 cases of TS, only 1 case with the karyotype of 45,X,/46,XX/46,XY was positive for all 5 loci. Of the 25 cases of Klinefelter syndrome, all were positive for all 5 loci. In one case of rare Klinefelter syndrome variants azoospermia factor（AZF） gene detection revealed the loss of the AZFa＋AZFb region. In 14 cases of 46,XX DSD, 7 cases were positive for SRY, 14 for ZFX, 7 for ZFY, 7 for ZYZ3, and 5 for DYZ1. PCR can complement and also confirm cytogenetic studies in the diagnosis of sex in cases of DSD.

Modern Health Worries and the Personality Disorders: Two Studies Using Different Measures

This paper reports on two studies using different measures of both Modern Health Worries (MHW) and the Personality Disorders (PDs) to establish the relationship between the two concepts. Study 1 used the PID-5 which is a measure of maladaptive personality traits and the extended 40 item MHW scale. Study 2 used the original 28 item measure of MHW and PDs as measured by the Coolidge Axis-II Inventory—Short Form: SCATI. In study 1 a regression on the total MHW scale accounted for 14% of the variance: those who scored higher on Antagonism and Negative Affect had higher MHW scores. In the study 2 regressions showed four variables consistently related to MHW: sex (females with higher scores), optimism, political beliefs (left wing liberals with higher scores) and those with Cluster B personality disorders (dramatic, overly emotional, erratic). There was enough overlap in the two studies to conclude that various PDs mainly from Cluster B (Moving Against others) were modestly related to MHW as predicted. Limitations and implications are considered.

Mechanism of sex hormone level in biological clock disorder induced acne and analysis of TCM Pathogenesis

Acne vulgaris is a common chronic inflammatory disease of pilosebaceous units. And sex hormone level disorder has became a hot research topic in the pathogenesis of acne. Studies show that the biological clock disorder can result in the disorder of sex hormone levels which causes or aggravates acne. Biological clock disorder coincides naturally with "sleep rhythm disorder" in Traditional Chinese Medicine(TCM). In this paper, we will discuss the modern medical mechanism of the biological clock disorder resulting in acne from the angle of sex hormones, and analyze the TCM pathogenesis of the disease caused by the disorder of the biological clock.

Male sex determination： insights into molecular mechanisms

Disorders of sex development often arise from anomalies in the molecular or cellular networks that guide the differentiation of the embryonic gonad into either a testis or an ovary, two functionally distinct organs. The activation of the Y-linked gene Sry （sex- determining region Y） and its downstream target Sox9 （Sry box-containing gene 9） triggers testis differentiation by stimulating the differentiation of Sertoli cells, which then direct testis morphogenesis. Once engaged, a genetic pathway promotes the testis development while actively suppressing genes involved in ovarian development. This review focuses on the events of testis determination and the struggle to maintain male fate in the face of antagonistic pressure from the underlying female programme.

HoLEP does not affect the overall sexual function of BPH patients： a prospective study

We aimed to prospectively evaluate the influence of holmium laser enucleation of the prostate （HoLEP） on the overall postoperative sexual function of benign prostatic hyperplasia （BPH） patients with lower urinary tract symptoms （LUTS） and to explore the relationship between sexual function and LUTS. From January 2010 to December 2011, sixty sexually active consecutive patients with BPH who underwent HoLEP were prospectively enrolled in the study. All patients filled out the Male Sexual Health Questionnaire （MSHQ） for evaluation of their overall sexual function and the International Prostatic Symptom Score （IPSS） for pre- and post-operative 6 months evaluation of their voiding symptoms. The LUTS and sexual function changes were statistically analyzed. The preoperative and 6 months postoperative status of the patients was compared using uroflowmetry and IPSS questionnaires. The analysis revealed significant improvements following HoLEP. Among the sub-domains of the MSHQ, postoperative sexual function, including erection, ejaculation, sexual satisfaction, anxiety or sexual desire, did not significantly change after HoLEP （P 〉 0.05）, whereas satisfaction scores decreased slightly due to retrograde ejaculation in 38 patients （63.3%）. Sexual satisfaction improved significantly and was correlated with the improvements of all LUTS and the quality-of-life （QoL） domains in IPSS after surgery （QoL; relative risk [RR]： -0.293; total symptoms, RR： -0.411; P 〈 0.05）. The nocturia score was associated with the erectile function score （odds ratio 0.318, P = 0.029）. The change in ejaculatory scores did not show significant association with IPSS scores. HoLEP did not influence overall sexual function, including erectile function. In addition, sexual satisfaction improved in proportion with the improvement of LUTS.

Connectivity differences between adult male and female patients with attention deficit hyperactivity disorder according to resting-state functional MRI

Attention deficit hyperactivity disorder（ADHD） is a pervasive psychiatric disorder that affects both children and adults. Adult male and female patients with ADHD are differentially affected, but few studies have explored the differences. The purpose of this study was to quantify differences between adult male and female patients with ADHD based on neuroimaging and connectivity analysis. Resting-state functional magnetic resonance imaging scans were obtained and preprocessed in 82 patients. Group-wise differences between male and female patients were quantified using degree centrality for different brain regions. The medial-, middle-, and inferior-frontal gyrus, superior parietal lobule, precuneus, supramarginal gyrus, superior- and middle-temporal gyrus, middle occipital gyrus, and cuneus were identified as regions with significant group-wise differences. The identified regions were correlated with clinical scores reflecting depression and anxiety and significant correlations were found. Adult ADHD patients exhibit different levels of depression and anxiety depending on sex, and our study provides insight into how changes in brain circuitry might differentially impact male and female ADHD patients.

45,X/47,XYY性发育异常一例并文献复习

45,X/47,XYY性发育异常是一种由于罕见的染色体异常导致的性发育异常疾病。报告1例收治的45,X/47,XYY嵌合型性发育异常患者,该患者主因原发性闭经并出现男性化表现就诊,具有特纳综合征(Turner syndrome,Turner综合征)的表现,腹腔镜探查显示一侧性腺为条索状,另一侧外观睾丸样,病理为卵睾型性腺,手术切除双侧附件并予人工周期治疗,有月经来潮。结合本例及检索到的文献报道的女性表型中因原发性闭经就诊的病例共11例,对该病的临床表现、诊断及治疗方式进行总结。女性表型45,X/47,XYY性发育异常患者临床表现多样,以Turner综合征表现合并男性化表现多见,应尽早发现并切除发育不良的性腺,防止性腺肿瘤的发生和男性化表现出现。术后进行长期激素替代治疗,同时注重患者精神心理的疏导。

17α羟化酶缺乏致46XY性发育异常:13例临床分析

目的:探讨社会性别为女性、染色体核型为46XY的17α羟化酶缺乏症(17OHD)的诊断及治疗。方法:回顾分析2006年1月至2023年1月就诊于郑州大学第一附属医院诊断为17OHD的社会性别为女性、核型为46XY的13例患者的临床资料。结果:13例17OHD患者的确诊平均年龄为(16.85±7.0)岁,确诊前外院漏诊、误诊5例。46XY的17OHD典型患者临床特点为第二性征不发育、原发性高促性腺激素性性腺功能低下性闭经、高血压、低血钾、皮质醇水平低、促肾上腺皮质激素(ACTH)水平高、肾上腺皮质增生、无子宫附件、骨龄落后于实际年龄。本研究中3例临床特征不典型患者通过P450c17(CYP17A1)基因检测确诊,1例为p.Thr329突变,1例p.Thr329和p.Thr307Ala复合突变。选择合适的糖皮质激素及性激素替代及手术可取得良好的预后。13例患者切除睾丸病理和未切除的睾丸影像学上均未发现恶性病变。结论:46XY 17OHD为罕见病,典型患者通过临床表现、辅助检查不难诊断,但有些患者并不具有典型临床表现,确诊年龄较晚。提示临床医生需提高对该疾病的认识,对于怀疑却临床特征不典型患者可通过P450c17(CYP17A1)基因检测确诊。对于青春期前渴望延迟睾丸切术者密切随访也未必不可接受,但安全性还需更多大量标本的积累。

儿童期17α-羟化酶/17,20碳链裂解酶缺陷症的临床及遗传学特征

目的探讨17α-羟化酶/17,20碳链裂解酶缺陷症(17α-hydroxylase/17,20-lyase deficiency,17OHD)在儿童期的临床及遗传学特征。方法回顾性分析2016年1月至2022年12月在郑州大学附属儿童医院确诊的4例17OHD患儿的临床表现、实验室及影像学检查结果、基因突变特点,并结合文献进行汇总分析。结果4例患儿确诊时,年龄为11月21天至10岁6月;染色体核型均为46,XY;社会性别为男性1例,女性3例;主诉为阴茎短小1例、腹股沟肿块1例、高血压2级2例;彩超检查分别在阴囊、腹股沟、腹股沟内环口发现睾丸3例。4例患儿8点皮质醇、睾酮、雄烯二酮水平均降低,促肾上腺皮质激素、孕酮、促黄体生成素、卵泡刺激素水平均升高,17羟孕酮均正常。3例患儿血钾轻度减低(3.44~3.48 mmol/L)。CYP17A1纯合突变1例,复合杂合突变3例,其中c.563 A>G和c.436+1G>T为未报道过的新突变位点,3例均存在c.985_987delinsAA变异;4例均接受口服氢化可的松治疗。结论外生殖器异常、腹股沟/阴唇包块及高血压是46,XY的17OHD儿童期的主要表现,早期规范治疗可减少并发症,CYP17A1 c.985_987delinsAA变异可能为我国17OHD患儿的热点变异。

4例46,XY性发育障碍患者遗传学分析

目的:探讨4例46,XY性发育障碍发生的分子机制。方法:收集患者临床病历资料,采集其肝素抗凝外周血进行淋巴细胞培养,染色体G显带技术制备并分析染色体核型,提取外周血DNA行SRY基因检测和测序,SRY基因检测结果阴性者外送标本行性发育相关基因靶向测序,生物信息学方法分析测序结果。结果:查体显示4例患者社会性别均为女性,而外周血淋巴细胞核型分析结果提示核型均为男性(46,XY),社会性别与生物学性别不一致;性别决定基因SRY均为阳性,测序结果提示病例1为SRY基因编码区第5位碱基缺失(c.del5A),病例2为SRY基因编码区第5位碱基发生错义突变(c.5A>T),病例3为SRY基因编码区第6位碱基缺失(c.del6A),病例4的SRY基因检测范围内未见突变位点,靶向测序结果提示雄激素受体基因(AR)编码区发生错义突变(c.2117 A>G);生物信息学软件Mutation taster提示c.del5A、c.del6A和c.2117 A>G等3种突变可能导致疾病发生,c.5A>T突变可能为人群多态现象;Raptor X蛋白质三维结构预测软件分析结果显示SRY基因c.5A>T突变对SRY蛋白的三维构象没有影响,而AR基因c.2117 A>G突变可导致AR蛋白的三维结构明显变化,并增加两个氢键;PolyPhen-2显示SRY基因c.5A>T和AR基因c.2117A>G突变为可能致病;ClinvAR软件分析结果提示4种突变均未见临床病例报道。结论:基因突变可能是导致患者性器官发育异常的原因,基因检测有助于明确诊断以及家庭再生育咨询。

46,XX卵睾型性发育障碍1例及文献复习

46,XX性发育障碍病因复杂,临床表现多样,诊断较为困难,本文通过对1例男性表型的46,XX的临床特点进行分析,并对该病的发病机制、临床表现、诊断及治疗等进行文献复习,以期提高临床医生对该类疾病的诊疗水平。

针刺联合中西药治疗肝郁肾虚型月经后期的疗效观察

目的 观察针刺联合中西药治疗肝郁肾虚型月经后期的临床疗效。方法 将88例肝郁肾虚型月经后期患者随机分为对照组(29例)、针刺组(29例)和联合组(30例)。对照组给予雌孕激素序贯疗法,针刺组在对照组基础上给予疏肝补肾针刺法,联合组在针刺组基础上给予疏肝益肾通瘀方治疗。观察3组治疗前后中医证候积分、性激素水平[雌二醇(estradial, E2)、促卵泡生成素(follicle-stimulating hormone, FSH)、促黄体生成素(luteinizing hormone, LH)水平、睾酮(testosterone, T)和催乳素(prolactin, PRL)]、卵巢功能(卵巢体积、卵泡最大直径、卵泡数量)和磷脂酰肌醇3-激酶(phosphoinositide 3-kinase, PI3K)/蛋白激酶B(protein kinase B, AKT)/哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)信号通路相关蛋白的变化,并比较3组临床疗效及安全性。结果 联合组总有效率为96.7%,高于对照组的72.4%(P<0.05);联合组与针刺组、针刺组与对照组比较,差异无统计学意义(P>0.05)。3组治疗后经色暗淡、腰骶酸痛、头晕耳鸣、性欲淡漠及烦躁易怒积分均低于治疗前(P<0.05);且联合组治疗后经色暗淡、腰骶酸痛、头晕耳鸣、性欲淡漠及烦躁易怒积分低于针刺组和对照组(P<0.05),针刺组低于对照组(P<0.05)。3组治疗后E2水平均高于治疗前(P<0.05),FSH、T、LH、PRL水平均低于治疗前(P<0.05);且联合组治疗后E2水平高于针刺组和对照组(P<0.05),针刺组高于对照组(P<0.05);联合组治疗后FSH、T、LH、PRL水平低于针刺组和对照组(P<0.05),针刺组低于对照组(P<0.05)。3组治疗后卵泡最大直径和卵泡数量均大于治疗前(P<0.05);且联合组治疗后卵泡最大直径和卵泡数量大于针刺组和对照组(P<0.05),针刺组大于对照组(P<0.05)。3组治疗前后卵巢体积比较,差异无统计学意义(P>0.05)。3组治疗后PI3K、Akt和m TOR蛋白表达浓度均高于治疗前(P<0.05);且联合组治疗后PI3K、Akt和mTOR蛋白表达浓度高于针刺组和对照组(P<0.05),针刺组高于对照组(P<0.05)。3组不良反应发生率比较,差异无统计学意义(P>0.05)。结论 针刺联合中西药可有效改善月经后期患者临床症状,调节性激素水平与卵巢功能,疗效显著,且安全性高,这可能与调控PI3K/Akt/m TOR信号通路有关。

全外显子组测序对性发育异常患者的分子遗传学病因分析

目的通过全外显子组测序(WES)技术分析性发育异常(DSD)患者的分子遗传学病因,以加深对DSD致病机制的认识。方法收集2008年3月-2021年8月于云南省第一人民医院就诊的60例DSD患者的临床资料进行回顾性分析,并对其中1个先证者进行家系研究。提取所有患者的外周血基因组DNA进行WES测序分析,WES结果利用SAMtools软件、单核苷酸多态性(SNP)数据库、InDel数据库进行SNP和InDel检测;采用ExomeDepth进行外显子水平的拷贝数变异(CNV)检测;应用PolyPhen-2、Mutation taster、PyMol软件进行突变的有害性预测,并采用Sanger进行测序验证。结果60例DSD患者中,22例为46,XX DSD,38例为46,XY DSD。22例46,XX DSD患者中14例存在SRY基因;在另外8例患者和其中1个先证者家系中,2例患者的NR5A1、PROKR2和ANOS1基因发生单核苷酸变异(SNV),4例患者中的CYP21A2基因发生CNV,其中CYP21A2 EX1 Dup已有该变异的相关致病性报道,其余3个CNV为意义未明的变异,2例未检出与DSD相关的基因突变位点。38例46,XY DSD患者WES分析结果中,14例中检出了10个致病或疑似致病变异位点,包括SRY、AR、SRD5A2、CYP17A1、NR5A1等5个基因;5例中检出CYP21A2、AKR1C2、CBX2、NR5A1基因的5个疑似致病的CNV,其中3个微缺失,2个微重复。WES结果中NR5A1(c.722G>T、c.48C>G)、ANOS1 c.564A>T变异为首次报道的位点,在检出的CNV中,CYP21A2 EX1 Dup在相关数据库中有致病性的报道,其余未见报道。结论WES技术的应用提高了对DSD的诊断能力,拓展了现有的DSD相关致病基因突变谱数据,丰富了对DSD致病机制的认识,可为开展遗传咨询提供帮助。

完全性雄激素不敏感综合征合并苗勒管残留临床特点的分析与探讨

【目的】分析完全性雄激素不敏感综合征(CAIS)合并苗勒管残留(MDR)患儿资料,并综述既往文献的报告,提高对CAIS的临床表现、病理生理的再认识。【方法】本研究通过对患儿病史回顾,体格检查,染色体、全外显子基因测序、促卵巢刺激素、黄体生成素、总睾酮、雌二醇、抗苗勒管激素、抑制素B、硫酸脱氢表雄酮、雄烯二酮、17羟孕酮等实验室检查,以及盆腔彩超、盆腔磁共振等影像学检查来诊断完全性雄激素不敏感综合征,并在腹腔镜下发现苗勒管结构。同时总结分析既往文献报道的完全性雄激素不敏感合并苗勒管结构类似病例。【结果】该患儿临床表现为女性表型,以原发性闭经来就诊,卵泡刺激素(FSH)、黄体生成素(LH)、睾酮升高,盆腔MRI示双侧隐睾,未见子宫附件,染色体核型46,XY,全外显子基因检测:AR基因半合子致病性变异c.2359C>T(p.Arg787*),AMH、AMHR2基因检测无异常。在腹腔镜下腹腔探查时发现发育不良睾丸及发育不良子宫。病理提示睾丸旁存在输卵管样结构。在数据库中共检索到基因确诊为CAIS并存MDR,且有详实数据的病例共11例。总结发现合并MDR的首诊表现、生化资料、性腺病理与无MDR的CAIS患者类似。【结论】本研究报道的CAIS患儿合并MDR,拓宽了CAIS的临床表现谱,为苗勒管退化的基础研究提供一种非依赖于AMH-AMHR2信号调控的思路。

肠道菌群与良性前列腺增生的关系和潜在机制

人体微生物群被定义为栖息在特定人体部分的共生微生物群,其中肠道微生物是人体最庞大的微生物群之一。近年来微生物组的研究为人类健康和疾病提供了新的视角,越来越多的研究表明肠道菌群失调与良性前列腺增生(benign prostatic hyperplasia,BPH)的进展有关。肠道菌群紊乱可能引起局部或全身炎症而影响BPH,由肠道微生物引起的性激素、胰岛素样生长因子1(insulin-like growth factor,IGF-1)等水平改变及代谢综合征(metabolic syndrome,MS)等可能参与BPH发展。此外,衰老及饮食等过程中肠道微生物组成的改变也可能是影响BPH的因素。本文着重于近年来肠道菌群与BPH的研究进展,并探讨肠道微生物如何通过炎症、性激素、IGF-1、MS、衰老和饮食等与BPH相关联,以期从调节肠道菌群的角度为BPH防治提供新思路和新方法。

完全型雄激素不敏感综合征合并无性细胞瘤一例

雄激素不敏感综合征(androgen insensitivity syndrome,AIS)临床较为罕见,早期诊断困难。报告1例完全型雄激素不敏感综合征(complete androgen insensitivity syndrome,CAIS)合并无性细胞瘤患者的诊治经过,患者因腹胀2 d,门诊行彩色超声提示盆腔肿物收入院,入院后先行盆腔肿物切除术治疗,因术前高雄激素血症原因不明,经染色体分析及基因检测最终明确诊断为CAIS合并无性细胞瘤,并最终行性腺恶性肿瘤根治术。目前该患者仍在密切随访中,病情稳定。通过回顾性分析该病例的临床特点及诊治经过,以期提高临床对于该病的认识。

Sex-biased single-cell genetic landscape in mice with autism spectrum disorder

Autistic spectrum disorder(ASD)is a male-biased,heterogeneous neurodevelopmental disorder that affects approximately 1%e2%of the population.Prenatal exposure to valproic acid(VPA)is a recognized risk factor for ASD,but the cellular and molecular basis of VPA-induced ASD at the single-cell resolution is unclear.Here,we aim to compare the cellular and molecular differences in the hippocampus between male and female prenatal mice with ASD at the single-cell transcriptomic level.The transcriptomes of more than 45,000 cells are assigned to 12 major cell types,including neurons,glial cells,vascular cells,and immune cells.Cell type-specific genes with altered expression after prenatal VPA exposure are analyzed,and the largest number of differentially expressed genes(DEGs)are found in neurons,choroid plexus epithelial cells,and microglia.In microglia,several pathways related to inflammation are found in both males and females,including the tumor necrosis factor(TNF),nuclear factor kappa B(NF-kB),toll-like receptor(TLR),and mitogen-activated protein kinase(MAPK)signaling pathways,which are important for the induction of autistic-like behavior.Additionally,we note that several X-linked genes,including Bex1,Bex3,and Gria3,were among the male-specific DEGs of neurons.This pioneering study describes the landscape of the transcriptome in the hippocampus of autistic mice.The elucidation of sexual differences could provide innovative strategies for the prevention and treatment of ASD.

Physical assessment and reference growth curves for children with 46,XY disorders of sex development

Importance:Impaired growth is an important factor in patients with disorders of sex development(DSD).Objective:To profile the growth of children with 46,XY DSD.Methods:We compared heights between 46,XY DSD children and normal boys and obtained growth curves for DSD using the k-median coefficient of variation method.The study subjects were categorized into groups with good response and poor response to the human chorionic gonadotrophin(HCG)test according to testosterone levels and were compared height standard deviation scores(HtSDS)with normal boys.Results:A total of 571 children with noncongenital adrenal hyperplasia(CAH)46,XY DSD were enrolled in this study.The overall HtSDS for the DSD subjects were 0.031 1.202.The HtSDS of DSD boys were lower than those for normal boys among multiple age groups since early infancy.In children aged≥12 years,the HtSDS values were significantly lower than the normal reference values for boys of the same age in both the good and poor response groups(P=.025 and P=.003,respectively).The HtSDS in the poor response group was generally lower than the normal reference value(P=.017).The average HtSDS values in the poor response groups were lower than those in the good response groups across multiple age groups.Interpretation:Growth retardation was evident in boys with non-CAH 46,XY DSD in early childhood and puberty.The level of growth retardation was related to testosterone level.DSD-specific growth curves can improve our understanding of growth dynamics and minimize the scope for bias in the assessment of growth in these children.

Management of children with disorders of sex development:20-year experience in southern Thailand

Background:Disorders of sex development(DSD)is a group of sexual differentiation disorders resulting in genital anomalies with defects in gonadal hormone synthesis and/or incomplete genital development.These conditions result in problems concerning the sex assignment of the child.This study aims to describe the clinical features,diagnosis and management of children with DSD in southern Thailand.Methods:The medical records of 117 pediatric patients diagnosed with DSD during the period of 1991-2011 were retrospectively reviewed.Results:Disorders of sex development were categorized into 3 groups:sex chromosome abnormalities(53.0%),46,XX DSD(29.9%)and 46,XY DSD(17.1%).The two most common etiologies of DSD were Turner syndrome(36.8%)and congenital adrenal hyperplasia(29.9%).Ambiguous genitalia/intersex was the main problem in 46,XX DSD(94%)and 46,XY DSD(100%).Sex reassignment was done in 5 children(4.3%)at age of 3-5 years:from male to female in 4 children(1 patient with congenital adrenal hyperplasia,1 patient with 45,X/46,XY DSD,and 2 patients with 46,XX ovotesticular DSD)and from female to male in 1 patient with 46,XX ovotesticular DSD.Of the total 20 children with 46,XY DSD,16(80%)were raised as females.Conclusion:Management of DSD children has many aspects of concern.Sex assignment/reassignment depends on the phenotype(phallus size)of the external genitalia rather than the sex chromosome.

Prevalence of gene mutations in a Chinese 46,XY disorders of sex development cohort detected by targeted next-generation sequencing

46,XY disorders of sex development(DSD)is characterized by incomplete masculinization genitalia,with gonadal dysplasia and with/without the presence of Mullerian structures.At least 30 genes related to 46,XY DSD have been found.However,the clinical phenotypes of patients with different gene mutations overlap,and accurate diagnosis relies on gene sequencing technology.Therefore,this study aims to determine the prevalence of pathogenic mutations in a Chinese cohort with 46,XY DSD by the targeted nextgeneration sequencing(NGS)technology.Eighty-seven 46,XY DSD patients were enrolled from the Peking Union Medical College Hospital(Beijing,China).A total of fifty-four rare variants were identified in 60 patients with 46,XY DSD.The incidence of these rare variants was approximately 69.0%(60/87).Twenty-five novel variants and 29 reported variants were identified.Based on the American College of Medical Genetics and Genomics(ACMG)guidelines,thirty-three variants were classified as pathogenic or likely pathogenic variants and 21 variants were assessed as variants of uncertain significance.The overall diagnostic rate was about 42.5%based on the pathogenic and likely pathogenic variants.Androgen receptor{AR),steroid 5-alpha-reductase 2(SRD5A2)and nuclear receptor subfamily 5 Group A member 1(NR5A1)gene variants were identified in 21,13 and 13 patients,respectively.The incidence of these three gene variants was about 78.3%(47/60)in patients with rare variants.It is concluded that targeted NGS is an effective method to detect pathogenic mutations in 46,XY DSD patients and AR,SRD5A2,and NR5A1 genes were the most common pathogenic genes in our cohort.