Genomic disorders ten years on

Genomic disorders are diseases that result from rearrangements of the human genome rather than from DNA sequence base changes. Moreover, such rearrangements occur because of architectural features of the genome that incite genome instability. The idea of genomic disorders emanated from locus-specific studies of the common autosomal dominant peripheral neuropathies: Charcot-Marie-Tooth disease type 1A (CMT1A; Mendelian Inheritance in Man (MIM) database ID 118220 [1]) and hereditary neuropathy with liability to pressure palsies (HNPP; MIM 162500). A careful re-read of the early reports on these conditions reveals nearly all the key concepts of genomic disorders, including genomic duplication [2,3] and deletion [4], gene dosage (PMP22) [5-8] and specific gene copy number variation (CNV) [6-8]. The concepts of genome architecture and low-copy repeats (LCRs) or segmental duplications (SDs) were well described before there was either a draft or a finished reference genome sequence [9,10] (Figure 1). The term LCR was first introduced by Bernice Morrow following her studies of DiGeorge syndrome (MIM 188400) rearrangement breakpoints [11] whereas the term SD was introduced by Evan Eichler [12,13] to explain his observations from genome-wide studies. The concepts of non-allelic homologous recombination (NAHR [9], although the specific term NAHR was not introduced until later [14]), reciprocal recombination resulting in duplication/deletion of the same genomic interval [9,10], recombination hotspots [15,16] and the effects of CNV (such as duplication) on the interpretation of the segregation of marker genotypes [2,17] also began to emerge at this early stage.Nevertheless, progress was blocked by both technological and conceptual limitations. Technically, we had no way to view the entire human genome simultaneously at a level of resolution that would enable insights into molecular mechanisms. Conceptually, locus-specific thinking had permeated genetics for over a century, with