The genomic basis of disease, mechanisms and assays for genomic disorders

Genome Dynamics
Paweł Stankiewicz, James R Lupski

Abstract

In the past fifteen years, an emerging group of genetic diseases have been described that result from DNA rearrangements rather than from single nucleotide changes. Such conditions have been referred to as genomic disorders. The predominant molecular mechanism underlying the rearrangements that cause this group of diseases and traits is nonallelic homologous recombination (NAHR) (unequal crossing-over between chromatids or chromosomes) utilizing low-copy repeats (LCRs) (also known as segmental duplications) as substrates. In contradistinction to highly repetitive sequences (e.g. Alu and LINE elements), these higher-order genomic architectural features usually span >1kb and up to hundreds of kilobases of genomic DNA, share >96% sequence identity and constitute >5% of the human genome. Many LCRs have complex structure and have arisen during primate speciation as a result of serial segmental duplications. LCRs can stimulate and/or mediate constitutional (both recurrent and nonrecurrent), evolutionary, and somatic rearrangements. Recently, copy-number variations (CNVs), also referred to as large-scale copy-number variations (LCVs) or copy-number polymorphisms (CNPs), parenthetically often associated with LCRs, have been demonstrate...Continue Reading

Citations

Jul 31, 2009·Nature·Christopher D PutnamRichard D Kolodner
Jan 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Claudia M B CarvalhoJames R Lupski
Apr 13, 2012·Critical Reviews in Biochemistry and Molecular Biology·Carolyn M George, Eric Alani
Jul 15, 2015·Briefings in Functional Genomics·Christina L Usher, Steven A McCarroll
Feb 16, 2019·BMC Genetics·Qinrui YangJianhui Xie
Jun 14, 2019·Molecular Syndromology·Fernanda T BelluccoMaria I Melaragno
Jul 9, 2011·American Journal of Medical Genetics. Part a·A NicoulazB Conrad
Dec 19, 2006·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Daniela del GaudioBenjamin B Roa

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