Copy number variation (CNV), encompassing losses or gains of relatively large genomic DNA segments, is one of the major sources of genetic diversity in humans. Recent studies revealed that de novo locus-specific mutation rates appear much higher for CNVs than for SNPs. Although several CNVs are presumably benign, the roles of CNVs in various disease pathogenesis have been increasingly emerged nowadays thanks to the sophisticated molecular laboratory technologies capable to detect various CNVs. At the beginning large CNVs appeared to be associated with genomic disorders only; however, it is now clear that CNVs can also be involved in susceptibilities to complex traits, and nowadays there is an emerging evidence that CNVs may cause Mendelian diseases or sporadic traits as well.

The disease-causing genomic rearrangements can be either recurrent or non-recurrent. Recombination-based as well as replication-based mechanisms have been proposed as responsible for the formation of CNVs such as nonallelic homologous recombination (NAHR), non-homologous end-joining (NHEJ), L1-mediated retrotransposition or Fork Stalling and Template Switching (FoSTeS). There is a variety of molecular mechanisms by which CNVs can lead to abnormal phenotypes, encompassing dosage sensitivity of a gene within the CNV, gene interruption or gene fusion at the breakpoint junctions, deletion of a regulatory element, or unmasking of a recessive alleles or functional polymorphism. Moreover, CNVs can affect noncoding regulatory elements such as promoters or enhancers as well.

The goal of this Research Topic is to provide the cutting-edge knowledge of CNVs leading to the development of rare disorders. Rare diseases are conditions that affect less than 5 in 10,000 people. To date more than 7000 entities exist and the numbers are continuously increasing. Today little is known about the genetic background of the majority of rare diseases, therefore their diagnostics is challenging. Furthermore, patients with undiagnosed genetic diseases often face a diagnostic odyssey, which lasts for eight years on average. CNVs were initially supposed to represent a significant contribution to rare disease formation; however, there is now evidence from a recent study that CNV should be responsible for the disease phenotype in approx. 10% of cases.

This Research Topic welcomes the submission of Original Research, Methods, Review and Mini-Review articles that cover, but are not limited to, the following topics:

• novel CNVs detected in rare disorder
• state- of the art technology for detection or evaluation of CNVs
• functional or animal studies related to the functional validation of CNVs
• comparative studies revealing phenotype –genotype correlation
• mechanism of non-coding CNVs in rare disorders and genotype-phenotype correlation

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Frontiers in Genetics

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