Mosaic variegated aneuploidy syndrome with tetraploid, and predisposition to male infertility triggered by mutant CEP192
Jihong Guo,
Wen-Bin He,
Lei Dai,
Fen Tian,
Zhenqing Luo,
Fang Shen,
Ming Tu,
Yu Zheng,
Liu Zhao,
Chen Tan,
Yongteng Guo,
Lan-Lan Meng,
Wei Liu,
Mei Deng,
Xinghan Wu,
Yu Peng,
Shuju Zhang,
Guang-Xiu Lu,
Ge Lin,
Hua Wang,
Yue-Qiu Tan,
Yongjia Yang
Affiliations
Jihong Guo
Department of Medical Genetics, Hunan Children’s Hospital, Xiangya Medical School & Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, China
Wen-Bin He
Hunan Guangxiu Hospital, Hunan Normal University School of Medicine, Changsha, China; Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, China
Lei Dai
Department of Obstetrics, Xiangya Hospital of Central South University, Changsha, China
Fen Tian
Department of Medical Genetics, Hunan Children’s Hospital, Xiangya Medical School & Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, China
Zhenqing Luo
Department of Medical Genetics, Hunan Children’s Hospital, Xiangya Medical School & Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, China
Fang Shen
Department of Medical Genetics, Hunan Children’s Hospital, Xiangya Medical School & Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, China
Ming Tu
Department of Medical Genetics, Hunan Children’s Hospital, Xiangya Medical School & Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, China
Yu Zheng
Department of Medical Genetics, Hunan Children’s Hospital, Xiangya Medical School & Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, China
Liu Zhao
Department of Medical Genetics, Hunan Children’s Hospital, Xiangya Medical School & Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, China
Chen Tan
Hunan Guangxiu Hospital, Hunan Normal University School of Medicine, Changsha, China; Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, China
Yongteng Guo
Hunan Guangxiu Hospital, Hunan Normal University School of Medicine, Changsha, China; Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, China
Lan-Lan Meng
Hunan Guangxiu Hospital, Hunan Normal University School of Medicine, Changsha, China; Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, China
Wei Liu
Department of Medical Genetics, Hunan Children’s Hospital, Xiangya Medical School & Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, China
Mei Deng
Department of Medical Genetics, Hunan Children’s Hospital, Xiangya Medical School & Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, China
Xinghan Wu
Department of Medical Genetics, Hunan Children’s Hospital, Xiangya Medical School & Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, China
Yu Peng
Department of Medical Genetics, Hunan Children’s Hospital, Xiangya Medical School & Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, China
Shuju Zhang
Department of Medical Genetics, Hunan Children’s Hospital, Xiangya Medical School & Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, China
Guang-Xiu Lu
Hunan Guangxiu Hospital, Hunan Normal University School of Medicine, Changsha, China; Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, China
Ge Lin
Hunan Guangxiu Hospital, Hunan Normal University School of Medicine, Changsha, China; Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, China
Hua Wang
Department of Medical Genetics, Hunan Children’s Hospital, Xiangya Medical School & Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, China
Yue-Qiu Tan
Hunan Guangxiu Hospital, Hunan Normal University School of Medicine, Changsha, China; Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, China; Corresponding author
Yongjia Yang
Department of Medical Genetics, Hunan Children’s Hospital, Xiangya Medical School & Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, China; Corresponding author
Summary: In this study, we report on mosaic variegated aneuploidy (MVA) syndrome with tetraploidy and predisposition to infertility in a family. Sequencing analysis identified that the CEP192 biallelic variants (c.1912C>T, p.His638Tyr and c.5750A>G, p.Asn1917Ser) segregated with microcephaly, short stature, limb-extremity dysplasia, and reduced testicular size, while CEP192 monoallelic variants segregated with infertility and/or reduced testicular size in the family. In 1,264 unrelated patients, variant screening for CEP192 identified a same variant (c.5750A>G, p.Asn1917Ser) and other variants significantly associated with infertility. Two lines of Cep192 mice model that are equivalent to human variants were generated. Embryos with Cep192 biallelic variants arrested at E7 because of cell apoptosis mediated by MVA/tetraploidy cell acumination. Mice with heterozygous variants replicated the predisposition to male infertility. Mouse primary embryonic fibroblasts with Cep192 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 mutant CEP192, which is a link for the MVA syndrome with tetraploidy and the predisposition to male infertility.
