Structural Variation in the Human Genome and its Role in Disease

Department of Molecular, Baylor College of Medicine, Houston, Texas 77030, USA.
Annual review of medicine (Impact Factor: 12.93). 02/2010; 61(1):437-55. DOI: 10.1146/annurev-med-100708-204735
Source: PubMed


During the last quarter of the twentieth century, our knowledge about human genetic variation was limited mainly to the heterochromatin polymorphisms, large enough to be visible in the light microscope, and the single nucleotide polymorphisms (SNPs) identified by traditional PCR-based DNA sequencing. In the past five years, the rapid development and expanded use of microarray technologies, including oligonucleotide array comparative genomic hybridization and SNP genotyping arrays, as well as next-generation sequencing with "paired-end" methods, has enabled a whole-genome analysis with essentially unlimited resolution. The discovery of submicroscopic copy-number variations (CNVs) present in our genomes has changed dramatically our perspective on DNA structural variation and disease. It is now thought that CNVs encompass more total nucleotides and arise more frequently than SNPs. CNVs, to a larger extent than SNPs, have been shown to be responsible for human evolution, genetic diversity between individuals, and a rapidly increasing number of traits or susceptibility to traits; such conditions have been referred to as genomic disorders. In addition to well-known sporadic chromosomal microdeletion syndromes and Mendelian diseases, many common complex traits including autism and schizophrenia can result from CNVs. Both recombination- and replication-based mechanisms for CNV formation have been described.

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    • "On the other hand, in ∼ 14–18% of children with developmental delay, a CNV larger than 400 kb may be phenotypically significant [Cooper et al., 2011; Hochstenbach et al., 2011]. Taken together, all classes of germline SVs occur more frequently than germline single nucleotide variations (SNVs), they affect more nucleotides and may have a greater phenotypic impact than SNVs [Stankiewicz and Lupksi, 2010; Campbell and Eichler, 2013]. Complex chromosome rearrangements (CCRs) are a class of SVs that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. "

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    • "A similar proportion of patients exhibit genetic intellectual disability syndromes such as Fragile X syndrome, Rett's syndrome, tuberous sclerosis, Joubert's syndrome, and more (review Geschwind 2008). Over the last decade, mainly because of the advent of exome sequencing, several thousands of genes have been implicated in this disease (Iossifov et al. 2012; Neale et al. 2012; O'Roak et al. 2012a,b; Pagnamenta et al. 2012; Sanders et al. 2012; Talkowski et al. 2012; Casanova 2014; Fromer et al. 2014; Iossifov et al. 2014; Stessman et al. 2014; Butler et al. 2015; Turner et al. 2015; Michaelson et al. 2012) (reviews Beaudet 2007; Abrahams and Geschwind 2008; Geschwind 2008; van de Lagemaat and Grant 2010; Stankiewicz and Lupski 2010; Miles 2011; Schaaf and Zoghbi 2011; Murdoch and State 2013; Stessman et al. 2014; Ronemus et al. 2014; Jeste and Geschwind 2014). The discovery of many genes has been facilitated by the Simons Simplex Collection (Fischbach and Lord 2010), and the accumulating data can be found in the Simons Foundation Autism Research Initiative (SFARI) web site ( "
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    • "Early studies of 22q11.2 deletions foreshadowed a more general role for rare CNV in understanding the global genetic architecture of schizophrenia in the population (Kirov et al. 2012; Costain et al. 2013; Stankiewicz and Lupski 2010; Lowther et al. 2015; Bassett et al. 2010; Hochstenbach et al. 2011; Costain and Bassett 2012; Zarrei et al. 2015; Rees et al. 2014). "
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