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

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 demonstrated as a source of human variation as well as a potential cause of diseases. In addition to fluorescence in situ hybridization (FISH), pulsed-field gel electrophoresis (PFGE), and in silico analyses, multiplex ligation-dependent probe amplification (MLPA), and array comparative genomic hybridization (aCGH) with BAC and PAC clones have proven to be useful diagnostic methods for the detection and characterization of DNA rearrangements with the latter enabling high-resolution genome-wide analysis. The clinical implementation of such techniques is revolutionizing clinical cytogenetics.