Cohen syndrome is an autosomal recessive disorder caused by VPS13B (COH1) gene mutations. This syndrome is significantly underdiagnosed and is characterized by intellectual disability, microcephaly, autistic symptoms, hypotension, myopia, retinal dystrophy, neutropenia, and obesity. VPS13B regulates intracellular membrane transport and supports the Golgi apparatus structure, which is critical for neuron formation. We generated induced pluripotent stem cells from two patients with pronounced manifestations of Cohen syndrome and differentiated them into neural stem cells and neurons. Using transmission electron microscopy, we documented multiple new ultrastructural changes associated with Cohen syndrome in the neuronal cells. We discovered considerable disturbances in the structure of some organelles: Golgi apparatus fragmentation and swelling, endoplasmic reticulum structural reorganization, mitochondrial defects, and the accumulation of large autophagosomes with undigested contents. These abnormalities underline the ultrastructural similarity of Cohen syndrome to many neurodegenerative diseases. The cell models that we developed based on patient-specific induced pluripotent stem cells can serve to uncover not only neurodegenerative processes, but the causes of intellectual disability in general.

Ring chromosome 18 is a rare chromosomal disorders that usually originate de novo and correlate with clinical manifestation: developmental delay as well as microcephaly, brain and ocular malformations, hypotonia and skeletal abnormalities. We generate iPSC clonal cell line ICGi024-A with pluripotency properties which were demonstrated in vitro by three germ layer differentiation capacity. ICGi024-A can be used for disease modeling and fundamental investigation of ring chromosome instability.

Transposon integration is influenced by genomic context, but the contribution of three-dimensional genome organization to transposon mobility remains poorly understood. Here, we developed T7-Mediated Unique-barcode Recovery sequencing (TMUR-seq), combining T7-based junction enrichment with uniquely barcoded Sleeping Beauty (SB) transposons to track secondary transposition events and their relationships to individual donor sites. Using this approach, we characterized genome-wide secondary SB transposition in human cells and analyzed the effects of genomic distance, donor-specific directionality, and chromatin organization on target selection. Secondary transposition was strongly dependent on linear genomic distance but showed pronounced donor-specific directional asymmetries, including recurrent mirror-image patterns at neighboring donor sites. Secondary integratiotes also showed enrichment for Hi-C contacts with their donor loci within approximately 50 kb after accounting for genomic distance, consistent with a contribution of local three-dimensional chromatin organization to target selection. An extended chromosome 2 donor cluster further illustrated how donor distribution, chromatin state, domain organization, and local three-dimensional connectivity can coincide with highly asymmetric integration patterns and regions of pronounced integration depletion. Together, these findings indicate that secondary SB transposition is not entirely random and is shaped by the combined effects of genomic distance and local genomic context. TMUR-seq provides a framework for tracking donor–recipient relationships and investigating the genomic determinants of transposon mobility.

Neurodevelopmental disorders, particularly autism spectrum disorder (ASD) and intellectual disability (ID), comprise a heterogeneous group characterized by a range of clinical phenotypes that are influenced by both genetic and environmental factors. ASD is notable for its diverse behavioral manifestations and varying cognitive profiles, which complicate the processes of diagnosis and intervention. In this study, we reprogrammed blood mononuclear cells from a patient with ASD, ID and multiple structural variations into induced pluripotent stem cells (iPSCs) using episomal vector transfection technology. The resulting iPSC line, designated ICGi058-A, demonstrated robust proliferation as compact colonies of cells with large nuclei and maintained karyotype 46,XY,inv(2)(p21q23);t(3;7)(p13;q11.2). Characterization of these iPSCs revealed the expression of key pluripotency markers, including OCT4, SOX2, NANOG and TRA-1-60. Moreover, the functional pluripotency of ICGi058-A was confirmed through the formation of embryoid bodies and successful differentiation into the three germ layers: ectoderm, mesoderm, and endoderm. Comprehensive genetic analysis (STR) showed that the derived iPSC line is identical to the original cell material obtained from the patient.