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

• DOI: 10.3389/fcell.2022.1025332
• Publication Date: 2022-11-16T06:59:35Z
• Authors: Julia Schmidt; Steffi Dreha-Kula...; Maria-Patapia Zaf...; Marie-Kristin Sch...; Bernd Wilken; Rudolf Funke; Christiane M Neuh...; Janine Altmüller; Holger Thiele; Peter Nürnberg; Saskia Biskup; Yun Li; Wolfram Hubertus ...; Silke Kaulfuß; Gökhan Yigit; Bernd Wollnik
• Keywords: 0303 health sciences; STAG2; QH301-705.5; Bioengineered Neuronal Organoids ; Cohesinopathies ; Mosaic Disorders ; Stag2 ; Supernumerary Nipples; Cell and Developmental Biology; 03 medical and health sciences; supernumerary nipples; bioengineered neuronal organoids; cohesinopathies; Technology Platforms; Genes, Cells and Cell-Based Medicine [Topic 1]; Biology (General); mosaic disorders

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 repair. A wide spectrum germline variants in genes encoding subunits or regulators complex have previously identified cause distinct but phenotypically overlapping multisystem developmental disorders belonging group cohesinopathies. Pathogenic rarely implicated an X-linked cohesinopathy associated with undergrowth, delay, dysmorphic features. Here, we describe for first time mosaic variant individual microcephaly, hemihypotrophy right side. We characterized grade mosaicism by deep sequencing analysis on extracted from EDTA blood, urine buccal swabs. Furthermore, report additional female novel de novo splice . Interestingly, both individuals show supernumerary nipples, feature that not reported before. Remarkably, transcripts showed only wildtype transcripts, even after blockage nonsense-mediated decay using puromycin blood lymphocytes. As phenotype -associated cohesinopathies dominated global severe brain abnormalities, investigated expression other related components during Bioengineered Neuronal Organoids (BENOs) generation RNA sequencing. observed prominent , especially between culture days 0 15, indicating essential function early development. In summary, expand genotypic phenotypic BENOs represent promising model gain further insights into critical role process nervous system