Disorders of the genome architecture: a review

Abstract

Genetic diseases are recognized to be one of the major categories of human disease. Traditionally genetic diseases are subdivided into chromosomal (numerical or structural aberrations), monogenic or Mendelian diseases, multifactorial/polygenic complex diseases and mitochondrial genetic disorders. A large proportion of these conditions occur sporadically. With the advent of newer molecular techniques, a number of new disorders and dysmorphic syndromes are delineated in detail. Some of these conditions do not conform to the conventional inheritance patterns and mechanisms are often complex and unique. Examples include submicroscopic microdeletions or microduplications, trinucleotide repeat disorders, epigenetic disorders due to genomic imprinting, defective transcription or translation due to abnormal RNA patterning and pathogenic association with single nucleotide polymorphisms and copy number variations. Among these several apparently monogenic disorders result from non-allelic homologous recombination associated with the presence of low copy number repeats on either side of the critical locus or gene cluster. The term 'disorders of genome architecture' is alternatively used to highlight these disorders, for example Charcot-Marie-Tooth type IA, Smith-Magenis syndrome, Neurofibromatosis type 1 and many more with an assigned OMIM number. Many of these so called genomic disorders occur sporadically resulting from largely non-recurrent de novo genomic rearrangements. Locus-specific mutation rates for genomic rearrangements appear to be two to four times greater than nucleotide-specific rates for base substitutions. Recent studies on several disease-associated recombination hotspots in male-germ cells indicate an excess of genomic rearrangements resulting in microduplications that are clinically underdiagnosed compared to microdeletion syndromes. Widespread application of high-resolution genome analyses may offer to detect more sporadic phenotypes resulting from genomic rearrangements involving de novo copy number variation.

Fig. 1

Molecular mechanisms for genomic disorders (Lupski and Stankiewicz 2005)—dashed lines indicate either deleted or duplicated region; the rearranged genomic interval is shown in brackets; gene is depicted by filled horizontal rectangle; regulatory gene is shown as horizontal hach-marked rectangle; asterisks denote point mutations

Fig. 2

Selected disorders of the genome architecture-Williams-Beuren syndrome (1); Beckwith-Wiedemann syndrome (2); Prader-Willi syndrome (3); Angelman syndrome (4); Smith-Magenis syndrome (5); CMTIA (6); Sotos syndrome (7);Neurofibromatosis-1 (8); 22q deletion syndrome (9,10)

Fig. 3

Mechanisms for non-allelic homologous recombination [NAHR] (Reproduced with permission from Nature Genetics, Turner et al. 2008)

Fig. 4

The 1.5 Mb duplicated chromosomal region of 17p12 including the PMP22 gene—note 500 kb junction fragment allele flanking the CMT1A gene detected by PFGE and Southern analysis. Note additional 17p segment (red colour) by metaphase (top two pictures) and interphase (lower two pictures) FISH (Reproduced with permission from Oxford University Press, New York)

Fig. 5

The unequal meiotic recombination (crossing-over) resulting in duplication [CMT1A] and deletion [HNPP]