CNVs in neurodevelopmental disorders
نویسندگان
چکیده
Copy number variations (CNVs) consist of duplications or deletions of chromosomal regions ranging from a few hundred to more than a million bases in size, and are likely to play a role in phenotypic diversity and evolution. Recent advances in the identification and mapping of CNVs among normal individuals and in model systems, using bioinformatics and hybridization-based methods, are beginning to shed light on the functional importance of CNVs. Most CNVs are harmless; however, some are associated with human diseases including neurodevelopmental disorders. Hundreds of CNVs have been linked to neurological phenotypes, including autism, schizophrenia, and bipolar disorder. Some CNVs, such as duplications involving VIPR2 on 7q36.3 and deletions of NRXN1 on 2p16.3 have been identified in autism, schizophrenia, and bipolar disorder [1, 2]. Nevertheless, there are many cases in which CNVs are present only in specific diseases. For example, duplication of WNT3 and WNT9B at 17q21.31-17q21.32 and the 3p14.1 deletion that includes FOXP1 are reported in autism [3]. These observations suggest that CNVs associated with neurodevelopmental disorders have global effects on the transcriptome, affording new strategies for the treatment or prevention of neurodevelopmental disorders. However, uncovering associations between copy number changes and complex diseases requires novel model systems to elucidate the different mechanisms by which they influence neural development. Recently, model systems for human genetic disorders have emerged based on the use of human pluripotent stem cells (hPSCs). These approaches include human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). These models offer unique advantages for the study of developmental biology. hPSCs can be differentiated into various types of somatic cells including neurons to examine molecular and cellular mechanisms involved in disease causation. Differentiated hiPSCs have enabled the development of human in vitro model systems that capture the inherent pathologies based on the genetic background of the source material. These stem cell lines derived from patients with various diseases offer unique advantages for the study of inherited neurological disorders. Such patient-specific hiPSCs allow examination of underlying genetic factors in human organ systems that affect neural development. MRI scans and post-mortem studies of autism spectrum disorders suggest abnormal brain development due to initial brain overgrowth followed by premature growth arrest [4]. Duplications of CNVs at the 17q21.31 and 17q21.32 regions have been reported in 25 genetic studies of autism (CNV catalog of SFARI Gene database). Of particular interest is the duplication mapping of chromosome 17q21.31-17q21.32 covering WNT3 …
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