Somatic mosaicism in STAG2 -associated cohesinopathies: Expansion of the genotypic and phenotypic spectrum.

Autor:	Schmidt J; Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany., Dreha-Kulaczewski S; Department of Pediatics and Adolescent Medicine, University Medical Center Göttingen, Göttingen, Germany., Zafeiriou MP; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany., Schreiber MK; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany., Wilken B; Department of Pediatric Neurology, Klinikum Kassel, Kassel, Germany., Funke R; Department of Pediatric Neurology, Klinikum Kassel, Kassel, Germany., Neuhofer CM; Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.; Institute of Neurogenomics, Helmholtz Zentrum Munich, Munich, Germany.; Department of Neurology, Friedrich-Baur-Institute, LMU Hospital, Ludwig Maximilians University, Munich, Germany., Altmüller J; Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine, University Hospital Cologne, Cologne, Germany.; Berlin Institute of Health at Charité, Core Facility Genomics, Berlin, Germany.; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Thiele H; Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine, University Hospital Cologne, Cologne, Germany., Nürnberg P; Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine, University Hospital Cologne, Cologne, Germany., Biskup S; CeGaT GmbH, Center for Genomics and Transcriptomics, Tübingen, Germany., Li Y; Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany., Zimmermann WH; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany., Kaulfuß S; Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany., Yigit G; Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany., Wollnik B; Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany.
Jazyk:	angličtina
Zdroj:	Frontiers in cell and developmental biology [Front Cell Dev Biol] 2022 Nov 16; Vol. 10, pp. 1025332. Date of Electronic Publication: 2022 Nov 16 (Print Publication: 2022).
DOI:	10.3389/fcell.2022.1025332
Abstrakt:	STAG2 is a component of the large, evolutionarily highly conserved cohesin complex, which has been linked to various cellular processes like genome organization, DNA replication, gene expression, heterochromatin formation, sister chromatid cohesion, and DNA repair. A wide spectrum of germline variants in genes encoding subunits or regulators of the cohesin complex have previously been identified to cause distinct but phenotypically overlapping multisystem developmental disorders belonging to the group of cohesinopathies. Pathogenic variants in STAG2 have rarely been implicated in an X-linked cohesinopathy associated with undergrowth, developmental delay, and dysmorphic features. Here, we describe for the first time a mosaic STAG2 variant in an individual with developmental delay, microcephaly, and hemihypotrophy of the right side. We characterized the grade of mosaicism by deep sequencing analysis on DNA extracted from EDTA blood, urine and buccal swabs. Furthermore, we report an additional female with a novel de novo splice variant in STAG2 . Interestingly, both individuals show supernumerary nipples, a feature that has not been reported associated to STAG2 before. Remarkably, additional analysis of STAG2 transcripts in both individuals showed only wildtype transcripts, even after blockage of nonsense-mediated decay using puromycin in blood lymphocytes. As the phenotype of STAG2 -associated cohesinopathies is dominated by global developmental delay, severe microcephaly, and brain abnormalities, we investigated the expression of STAG2 and other related components of the cohesin complex during Bioengineered Neuronal Organoids (BENOs) generation by RNA sequencing. Interestingly, we observed a prominent expression of STAG2 , especially between culture days 0 and 15, indicating an essential function of STAG2 in early brain development. In summary, we expand the genotypic and phenotypic spectrum of STAG2 -associated cohesinopathies and show that BENOs represent a promising model to gain further insights into the critical role of STAG2 in the complex process of nervous system development. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Schmidt, Dreha-Kulaczewski, Zafeiriou, Schreiber, Wilken, Funke, Neuhofer, Altmüller, Thiele, Nürnberg, Biskup, Li, Zimmermann, Kaulfuß, Yigit and Wollnik.)
Databáze:	MEDLINE
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