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      Mosaic variegated aneuploidy syndrome with tetraploid, and predisposition to male infertility triggered by mutant CEP192

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          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.

          Abstract

          This paper reports a disease gene CEP192 that drives tetraploidy (whole-genome doubling) formation and links to two human disorders, the MVA (plus tetraploidy) syndrome and the predisposition to male infertility.

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          Predicting Splicing from Primary Sequence with Deep Learning

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            The evolutionary history of 2,658 cancers

            Cancer develops through a process of somatic evolution 1,2 . Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes 3 . Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) 4 , we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.
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              Genetics of mammalian meiosis: regulation, dynamics and impact on fertility.

              Meiosis is an essential stage in gamete formation in all sexually reproducing organisms. Studies of mutations in model organisms and of human haplotype patterns are leading to a clearer understanding of how meiosis has adapted from yeast to humans, the genes that control the dynamics of chromosomes during meiosis, and how meiosis is tied to gametic success. Genetic disruptions and meiotic errors have important roles in infertility and the aetiology of developmental defects, especially aneuploidy. An understanding of the regulation of meiosis, coupled with advances in genomics, may ultimately allow us to diagnose the causes of meiosis-based infertilities, more wisely apply assisted reproductive technologies, and derive functional germ cells.
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                Author and article information

                Contributors
                Journal
                HGG Adv
                HGG Adv
                Human Genetics and Genomics Advances
                Elsevier
                2666-2477
                19 November 2023
                11 January 2024
                19 November 2023
                : 5
                : 1
                : 100256
                Affiliations
                [1 ]Department of Medical Genetics, Hunan Children’s Hospital, Xiangya Medical School & Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, China
                [2 ]Hunan Guangxiu Hospital, Hunan Normal University School of Medicine, Changsha, China
                [3 ]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
                [4 ]Department of Obstetrics, Xiangya Hospital of Central South University, Changsha, China
                Author notes
                []Corresponding author tanyueqiu@ 123456csu.edu.cn
                [∗∗ ]Corresponding author yongjia727@ 123456aliyun.com
                [5]

                These authors contributed equally

                [6]

                Lead contact

                Article
                S2666-2477(23)00088-X 100256
                10.1016/j.xhgg.2023.100256
                10716027
                37981762
                e03d5f5a-f655-4efc-8819-57686152ca75
                © 2023 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 3 August 2023
                : 15 November 2023
                Categories
                Article

                mosaic variegated aneuploidy,tetraploidy,male infertility,cep192 mutation

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