Mosaic variegated aneuploidy syndrome with tetraploid, and predisposition to male infertility triggered by mutantCEP192
Authors: Guo Jihong , He Wen-bin , Dai Lei , Tian Fen , Luo Zhenqing , Shen Fang , Tu Ming , Zheng Yu , Zhao Liu , Tan Chen , Guo Yongteng , Meng Lan-Lan , Liu Wei , Deng Mei , Wu Xinghan , Peng Yu , Zhang Shuju , Lu Guang-Xiu , Lin Ge , Wang Hua , Tan Yue-Qiu , Yang Yongjia 
Published: July 2023

AbstractIn the present study, we report on mosaic variegated aneuploidy (MVA) syndrome with tetraploidy and predisposition to infertility in a family. Sequencing analysis identified that theCEP192biallelic variants (c.1912C>T/p.H638Y and c.5750A>G/p.N1917S) segregated with microcephaly, short stature, limb–extremity dysplasia, and reduced testicular size, whileCEP192monoallelic variants segregated with infertility and/or reduced testicular size in the family. In 1,264 unrelated patients, variant screening forCEP192identified a same variant (c.5750A>G/p.N1917S) and other variants significantly associated with infertility. Two lines ofCep192mice model that are equivalent to human variants were generated. Embryos withCep192-biallelic variants arrested at E7 because of cell apoptosis mediated by MVA/tetraploidy cells’ acumination. Mice with heterozygous variants replicated the predisposition to male infertility. Mouse primary embryonic fibroblasts withCep192-biallelic variants cultured in vitro showed abnormal morphology, mitotic arresting, and disruption of spindle-formation. In patient epithelial cells with biallelic variants cultured in vitro, the number of cells arrested during the prophase increased because of the failure of spindle formation. Accordingly, we present a novel disease geneCEP192,which as a link for the MVA syndrome with tetraploidy and the predisposition to male infertility.In the present study, we report on mosaic variegated aneuploidy (MVA) syndrome with tetraploidy and predisposition to infertility in a family. Sequencing analysis identified that theCEP192biallelic variants (c.1912C>T/p.H638Y and c.5750A>G/p.N1917S) segregated with microcephaly, short stature, limb–extremity dysplasia, and reduced testicular size, whileCEP192monoallelic variants segregated with infertility and/or reduced testicular size in the family. In 1,264 unrelated patients, variant screening forCEP192identified a same variant (c.5750A>G/p.N1917S) and other variants significantly associated with infertility. Two lines ofCep192mice model that are equivalent to human variants were generated. Embryos withCep192-biallelic variants arrested at E7 because of cell apoptosis mediated by MVA/tetraploidy cells’ acumination. Mice with heterozygous variants replicated the predisposition to male infertility. Mouse primary embryonic fibroblasts withCep192-biallelic variants cultured in vitro showed abnormal morphology, mitotic arresting, and disruption of spindle-formation. In patient epithelial cells with biallelic variants cultured in vitro, the number of cells arrested during the prophase increased because of the failure of spindle formation. Accordingly, we present a novel disease geneCEP192,which as a link for the MVA syndrome with tetraploidy and the predisposition to male infertility.