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Mol Neurobiol. 2018 Aug;55(8):6533-6546. doi: 10.1007/s12035-017-0851-5. Epub 2018 Jan 11.

Allele-Specific Biased Expression of the CNTN6 Gene in iPS Cell-Derived Neurons from a Patient with Intellectual Disability and 3p26.3 Microduplication Involving the CNTN6 Gene.

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Institute of Cytology and Genetics SB RAS, Novosibirsk, 630090, Russia.
Novosibirsk State University, Novosibirsk, 630090, Russia.
Institute of Molecular Biology and Biophysics, Novosibirsk, 630117, Russia.
Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, 630090, Russia.
Research Institute of Medical Genetics, Tomsk National Research Medical Center Russian Academy of Sciences, Tomsk, 634050, Russia.
Siberian State Medical University, Tomsk, 634050, Russia.
Institute of Cytology and Genetics SB RAS, Novosibirsk, 630090, Russia.
Novosibirsk State University, Novosibirsk, 630090, Russia.


Copy number variations (CNVs) of the human CNTN6 gene caused by megabase-scale microdeletions or microduplications in the 3p26.3 region are often the cause of neurodevelopmental disorders, including intellectual disability and developmental delay. Surprisingly, patients with different copy numbers of this gene display notable overlapping of neuropsychiatric symptoms. The complexity of the study of human neuropathologies is associated with the inaccessibility of brain material. This problem can be overcome through the use of reprogramming technologies that permit the generation of induced pluripotent stem (iPS) cells from fibroblasts and their subsequent in vitro differentiation into neurons. We obtained a set of iPS cell lines derived from a patient carrier of the CNTN6 gene duplication and from two healthy donors. All iPS cell lines displayed the characteristics of pluripotent cells. Some iPS cell lines derived from the patient and from healthy donors were differentiated in vitro by exogenous expression of the Ngn2 transcription factor or by spontaneous neural differentiation of iPS cells through the neural rosette stage. The obtained neurons showed the characteristics of mature neurons as judged by the presence of neuronal markers and by their electrophysiological characteristics. Analysis of allele-specific expression of the CNTN6 gene in these neuronal cells by droplet digital PCR demonstrated that the level of expression of the duplicated allele was significantly reduced compared to that of the wild-type allele. Importantly, according to the sequencing data, both copies of the CNTN6 gene, which were approximately 1 Mb in size, showed no any additional structural rearrangements.


3p26.3 microduplication; Allele-specific expression; CNTN6 gene; Induced pluripotent stem cells; Intellectual disability; in vitro neural differentiation

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