Klinefelter syndrome (KS; 47,XXY) is the most common sex chromosomal anomaly and causes a multitude of symptoms. Often the most noticeable symptom is infertility caused by azoospermia with testicular histology showing hyalinization of tubules, germ cells loss, and Leydig cell hyperplasia. The germ cell loss begins early in life leading to partial hyalinization of the testis at puberty, but the mechanistic drivers behind this remain poorly understood. In this systematic review, we summarize the current knowledge on developmental changes in the cellularity of KS gonads supplemented by a comparative analysis of the fetal and adult gonadal transcriptome, and blood transcriptome and methylome of men with KS. We identified a high fraction of upregulated genes that escape X‐chromosome inactivation, thus supporting previous hypotheses that these are the main drivers of the testicular phenotype in KS. Enrichment analysis showed overrepresentation of genes from the X‐ and Y‐chromosome and testicular transcription factors. Furthermore, by re‐evaluation of recent single cell RNA‐sequencing data originating from adult KS testis, we found novel evidence that the Sertoli cell is the most affected cell type. Our results are consistent with disturbed cross‐talk between somatic and germ cells in the KS testis, and with X‐escapee genes acting as mediators.

中文翻译：

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来自47，XXY Klinefelter综合征男性血液和睾丸组织的转录组学和甲基组学数据的整合和再分析表明，睾丸支持细胞主要参与了睾丸支持细胞的形成。

Klinefelter综合征（KS; 47，XXY）是最常见的性染色体异常，并引起多种症状。通常最明显的症状是由无精子症引起的不育，睾丸组织学表现为小管透明质化，生殖细胞丢失和Leydig细胞增生。生殖细胞的损失从生命的早期开始，导致青春期睾丸部分透明化，但其背后的机制驱动因素仍知之甚少。在本系统综述中，我们总结了KS性腺细胞性发展变化的当前知识，并通过对KS男性和胎儿的性腺和成年性腺转录组，血液转录组和甲基化组的比较分析进行了补充。我们确定了逃避X染色体失活的大部分上调基因，因此支持了先前的假设，这些假设是KS中睾丸表型的主要驱动因素。富集分析显示X和Y染色体和睾丸转录因子的基因过分表达。此外，通过对来自成年KS睾丸的近期单细胞RNA测序数据的重新评估，我们发现了新的证据表明支持细胞是受影响最大的细胞类型。我们的结果与KS睾丸中体细胞和生殖细胞之间受干扰的串扰以及X逃逸基因充当介体的现象一致。我们发现新的证据表明Sertoli细胞是受影响最大的细胞类型。我们的结果与KS睾丸中体细胞和生殖细胞之间受干扰的串扰以及X逃逸基因充当介体的现象一致。我们发现新的证据表明Sertoli细胞是受影响最大的细胞类型。我们的结果与KS睾丸中体细胞和生殖细胞之间受干扰的串扰以及X逃逸基因充当介体的现象一致。