Vorsanova Svetlana G, Demidova Irina A, Kolotii Alexey D, Kurinnaia Oksana S, Kravets Victor S, Soloviev Ilya V, Yurov Yuri B, Iourov Ivan Y
Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University, Ministry of Health of Russian Federation, 125412, Moscow, Russia.
Yurov's Laboratory of Molecular Genetics and Cytogenomics of the Brain, Mental Health Research Center, Moscow, 115522, Russia.
Mol Cytogenet. 2022 Mar 5;15(1):8. doi: 10.1186/s13039-022-00588-z.
Klinefelter syndrome is a common chromosomal (aneuploidy) disorder associated with an extra X chromosome in males. Regardless of numerous studies dedicated to somatic gonosomal mosaicism, Klinefelter syndrome mosaicism (KSM) has not been systematically addressed in clinical cohorts. Here, we report on the evaluation of KSM in a large cohort of boys with neurodevelopmental disorders. Furthermore, these data have been used for an extension of the hypothesis, which we have recently proposed in a report on Turner's syndrome mosaicism in girls with neurodevelopmental disorders.
Klinefelter syndrome-associated karyotypes were revealed in 49 (1.1%) of 4535 boys. Twenty one boys (0.5%) were non-mosaic 47,XXY individuals. KSM was found in 28 cases (0.6%) and manifested as mosaic aneuploidy (50,XXXXXY; 49,XXXXY; 48,XXXY; 48,XXYY; 47,XXY; and 45,X were detected in addition to 47,XXY/46,XY) and mosaic supernumerary marker chromosomes derived from chromosome X (ring chromosomes X and rearranged chromosomes X). It is noteworthy that KSM was concomitant with Rett-syndrome-like phenotypes caused by MECP2 mutations in 5 boys (0.1%).
Our study provides data on the occurrence of KSM in neurodevelopmental disorders among males. Accordingly, it is proposed that KSM may be a possible element of pathogenic cascades in psychiatric and neurodegenerative diseases. These observations allowed us to extend the hypothesis proposed in our previous report on the contribution of somatic gonosomal mosaicism (Turner's syndrome mosaicism) to the etiology of neurodevelopmental disorders. Thus, it seems to be important to monitor KSM (a possible risk factor or a biomarker for adult-onset multifactorial brain diseases) and analysis of neuromarkers for aging in individuals with Klinefelter syndrome. Cases of two or more supernumerary chromosomes X were all associated with KSM. Finally, Rett syndrome-like phenotypes associated with KSM appear to be more common in males with neurodevelopmental disorders than previously recognized.
克兰费尔特综合征是一种常见的染色体（非整倍体）疾病，男性患者多了一条X染色体。尽管有许多关于体细胞性染色体镶嵌现象的研究，但克兰费尔特综合征镶嵌现象（KSM）在临床队列中尚未得到系统研究。在此，我们报告了对一大群神经发育障碍男孩中KSM的评估。此外，这些数据已用于扩展我们最近在一份关于神经发育障碍女孩特纳综合征镶嵌现象的报告中提出的假设。
在4535名男孩中，49名（1.1%）被发现有克兰费尔特综合征相关的核型。21名男孩（0.5%）为非镶嵌型47,XXY个体。在28例（0.6%）中发现了KSM，表现为镶嵌非整倍体（除47,XXY/46,XY外，还检测到50,XXXXXY；49,XXXXY；48,XXXY；48,XXYY；47,XXY；以及45,X）和源自X染色体的镶嵌额外标记染色体（环状X染色体和重排X染色体）。值得注意的是，5名男孩（0.1%）的KSM与由MECP2突变引起的雷特综合征样表型同时出现。
我们的研究提供了男性神经发育障碍中KSM发生率的数据。因此，有人提出KSM可能是精神疾病和神经退行性疾病致病级联反应的一个可能因素。这些观察结果使我们能够扩展我们之前关于体细胞性染色体镶嵌现象（特纳综合征镶嵌现象）对神经发育障碍病因学贡献的报告中提出的假设。因此，监测KSM（成人多因素脑疾病的一个可能危险因素或生物标志物）以及分析克兰费尔特综合征患者的衰老神经标志物似乎很重要。两条或更多额外X染色体的病例均与KSM相关。最后，与KSM相关的雷特综合征样表型在患有神经发育障碍的男性中似乎比以前认识到的更为常见。
