Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, Denmark.
Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
Am J Med Genet C Semin Med Genet. 2020 Jun;184(2):216-225. doi: 10.1002/ajmg.c.31802. Epub 2020 Jun 2.
Since the first description of Klinefelter syndrome (KS) was published in 1942 in The Journal of Clinical Endocrinology, large inter-individual variability in the phenotypic presentation has been demonstrated. However, our understanding of the global impact of the additional X chromosome on the genome remains an enigma. Evidence from the existing literature of KS indicates that not just one single genetic mechanism can explain the phenotype and the variable expressivity, but several mechanisms may be at play concurrently. In this review, we describe different genetic mechanisms and recent advances in the understanding of the genome, epigenome, and transcriptome of KS and the link to the phenotype and clinical heterogeneity. Future studies are needed to unite clinical data, genomic data, and basic research attempting to understand the genetics behind KS. Unraveling the genetics of KS will be of clinical relevance as it may enable the use of polygenic risk scores to predict future disease susceptibility and enable clinical risk stratification of KS patients in the future.
自 1942 年《临床内分泌学杂志》首次描述克莱恩费尔特综合征（KS）以来，已经证明了表型表现存在很大的个体间变异性。然而，我们对额外 X 染色体对基因组的全球影响的理解仍然是一个谜。来自 KS 现有文献的证据表明，不仅仅有一种单一的遗传机制可以解释表型和可变表达性，而是可能同时存在几种机制。在这篇综述中，我们描述了不同的遗传机制以及对 KS 的基因组、表观基因组和转录组的理解的最新进展，并探讨了其与表型和临床异质性的联系。未来的研究需要将临床数据、基因组数据和试图理解 KS 背后遗传学的基础研究结合起来。阐明 KS 的遗传学将具有临床相关性，因为它可能使多基因风险评分能够预测未来的疾病易感性，并使 KS 患者能够在未来进行临床风险分层。
