Institute of Medical Genetics, Linyi People's Hospital, Shandong 276003, China.
BGI, 11-2 Building, Northern Industry District, Shenzhen 518083, China.
Gene. 2014 Aug 15;547(1):43-9. doi: 10.1016/j.gene.2014.06.007. Epub 2014 Jun 14.
It is widely accepted that the incidence of chromosomal aberration is 10-15.2% in the azoospermic male; however, the exact genetic damages are currently unknown for more than 40% of azoospermia. To elucidate the causative gene defects, we used the next generation sequencing (NGS) to map the breakpoints of a chromosome insertion from an azoospermic male who carries a balanced, maternally inherited karyotype 46, XY, inv ins (18,7) (q22.1; q36.2q21.11). The analysis revealed that the breakage in chromosome 7 disrupts two genes, dipeptidyl aminopeptidase-like protein 6 (DPP6) and contactin-associated protein-like 2 (CACNA2D1), the former participates in regulation of voltage-gated potassium channels, and the latter is one of the components in voltage-gated calcium channels. The deletion and duplication were not identified equal or beyond 100 kb, but 4 homologous DNA elements were verified proximal to the breakpoints. One of the proband's sisters inherited the same aberrant karyotype and experienced recurrent miscarriages and consecutive fetus death, while in contrast, another sister with a normal karyotype experienced normal labor and gave birth to healthy babies. The insertional translocation is confirmed with FISH and the Y-chromosome microdeletions were excluded by genetic testing. This is the first report describing chromosome insertion inv ins (18,7) and attributes DPP6 and CACNA2D1 to azoospermia.
人们普遍认为，在无精子症男性中，染色体畸变的发生率为 10-15.2%；然而，目前仍有超过 40%的无精子症患者的具体遗传损伤原因未知。为了阐明导致这种疾病的基因缺陷，我们使用下一代测序（NGS）技术对一名携带平衡、母系遗传核型 46，XY，inv ins（18,7）（q22.1；q36.2q21.11）的无精子症男性的染色体插入断点进行了定位。分析结果显示，7 号染色体的断裂破坏了两个基因，二肽基肽酶样蛋白 6（DPP6）和接触蛋白相关蛋白样 2（CACNA2D1），前者参与电压门控钾通道的调节，后者是电压门控钙通道的组成部分之一。缺失和重复未被确定为等于或超过 100kb，但在断点附近验证了 4 个同源 DNA 元件。先证者的一位姐妹继承了相同的异常核型，经历了反复流产和连续胎儿死亡，而另一位具有正常核型的姐妹则经历了正常分娩并生下了健康的婴儿。通过荧光原位杂交（FISH）证实了插入易位的存在，并通过基因检测排除了 Y 染色体微缺失。这是首例描述染色体插入 inv ins（18,7）并将 DPP6 和 CACNA2D1 与无精子症相关联的报告。
