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Disorders of the Genome Architecture: a Review Genomic Med. (2008) 2:69–76 DOI 10.1007/s11568-009-9028-2 REVIEW ARTICLE Disorders of the genome architecture: a review Dhavendra Kumar Received: 22 July 2008 / Revised: 17 December 2008 / Accepted: 13 February 2009 / Published online: 11 March 2009 Ó Springer Science+Business Media B.V. 2009 Abstract Genetic diseases are recognized to be one of hotspots in male-germ cells indicate an excess of genomic the major categories of human disease. Traditionally rearrangements resulting in microduplications that are genetic diseases are subdivided into chromosomal clinically underdiagnosed compared to microdeletion syn- (numerical or structural aberrations), monogenic or Men- dromes. Widespread application of high-resolution genome delian diseases, multifactorial/polygenic complex diseases analyses may offer to detect more sporadic phenotypes and mitochondrial genetic disorders. A large proportion of resulting from genomic rearrangements involving de novo these conditions occur sporadically. With the advent of copy number variation. newer molecular techniques, a number of new disorders and dysmorphic syndromes are delineated in detail. Some Keywords Genome Á Genome architecture Á of these conditions do not conform to the conventional Genomic disorder Á Genomic rearrangements Á inheritance patterns and mechanisms are often complex Mendelian disease Á Sporadic disease Á De novo mutations Á and unique. Examples include submicroscopic microdele- Malformation syndrome tions or microduplications, trinucleotide repeat disorders, epigenetic disorders due to genomic imprinting, defective transcription or translation due to abnormal RNA pattern- Introduction ing and pathogenic association with single nucleotide polymorphisms and copy number variations. Among these Developments in genetics and molecular biology have several apparently monogenic disorders result from non- provided a vast amount of data and information to support allelic homologous recombination associated with the the view that most human diseases have a significant presence of low copy number repeats on either side of the genetic component. Characterization of the genetic deter- critical locus or gene cluster. The term ‘disorders of gen- minants of disease provides remarkable opportunities for ome architecture’ is alternatively used to highlight these clinical medicine through an improved understanding of disorders, for example Charcot-Marie-Tooth type IA, pathogenesis, diagnosis and therapeutic options. An Smith-Magenis syndrome, Neurofibromatosis type 1 and understanding of the genetic basis of human disease has many more with an assigned OMIM number. Many of opened the way forward for a new taxonomy of human these so called genomic disorders occur sporadically disease that will be free from limitations and bias in resulting from largely non-recurrent de novo genomic developing diagnostic criteria related to events which are rearrangements. Locus-specific mutation rates for genomic often secondary and peripheral to its cause (Bell 2003). For rearrangements appear to be two to four times greater than instance, genetic information has allowed us to identify nucleotide-specific rates for base substitutions. Recent distinct forms of diabetes mellitus, defining an auto- studies on several disease-associated recombination immune form associated with highly diverse and complex human leukocyte antigens [HLA] and other factors that affect both expression and modification of gene products in D. Kumar (&) Institute of Medical Genetics, Cardiff University, Cardiff, UK mediating the adult form of the disease (Cardon and Bell e-mail: [email protected] 2001). Similarly, a number of genetically determined 123 70 Genomic Med. (2008) 2:69–76 molecules and pathways have been characterized that are Table 1 Classification of genomic disorders crucial in the pathogenesis of bronchial asthma. It is now Disorders of genome architecture (genomic rearrangements) widely believed that a clearer understanding of the mech- Disorders of genome architecture (genomic rearrangements) anisms and pathways of a disease will assist us in Tri-nucleotide repeats disorders (genomic instability) delineating distinct disease subtypes, and may resolve Chromosome breakage disorders (genomic instability) many questions relating to variable disease symptoms, Non-dysjunction disorders (genomic instability) progression and response to therapy. This might help in Complex genomic diseases (genomic variation-SNPs/CNVs) revising the current diagnostic criteria. Eventually, genetics may contribute to a new taxonomy of human disease for clinical practice. (Table 1). A number of hereditary disorders present with Although genetics is acknowledged to be an important complex genetic pathology that do not follow the con- aspect in understanding the pathogenesis of disease, ventional principles of inheritance. There is now genetic classification of human disease has not yet received overwhelming evidence within these disorders that indi- full recognition. There is ample evidence in support of the cates unusual mechanisms suggesting ‘non-traditional argument that genetic factors are probably associated with inheritance’. The mechanisms involve certain genomic all human diseases except probably for trauma. It is argued regions that directly or indirectly influence regulation and that the outcomes to trauma might be influenced by expression of one or more genes manifesting in complex inherited factors such as genetically determined inflam- phenotypes. Currently some of these disorders are either matory markers, host-response to infection and tissue listed as chromosomal or single-gene disorders. damage. Various categories of genetic disorders are con- sidered to be rare with a tendency to be included under the broad title of organ-system diseases. Often these are listed Phenotypes of disorders of genome architecture as simply etiological factors rather than a distinct disease category. This concept and approach is now rapidly being Recent completion of the human genome project and outdated and replaced with new classes of diseases. This sequencing of the total genomes of yeast and other bacte- progress is seriously hampered by the lack of formal edu- rial species have enabled investigators to view genetic cation at all levels and integration of appropriate information in the context of the entire genome. As a result technologies into the modern medical diagnostic and it is now possible to recognize mechanisms of some genetic therapeutic infrastructure. diseases at the genomic level. The evolution of the mam- Traditionally, genetic diseases are classified as chro- malian genome has resulted in the duplication of genes, mosomal (numerical or structural), Mendelian or single- gene segments and repeat gene clusters (Lupski 1998). This gene disorders, multifactorial/polygenic complex diseases aspect of genome architecture provides recombination hot or congenital anomalies and diseases associated with spe- spots between nonsyntenic regions of chromosomes that cific mitochondrial gene mutations. Apart from are distributed across the whole genome. These genomic chromosomal disorders, essentially all genetic disorders regions become susceptible to further DNA rearrangements result from some form of alteration or mutation occurring that may be associated with an abnormal phenotype. Such in a specific gene (single gene diseases) or involving disorders are collectively grouped under the broad category multiple loci spread across the human genome (polygenic of ‘genome architecture disorders’. disorders). The major impact of chromosomal disorders The term ‘genome architecture disorder’ refers to a occurs before birth and carries a serious health burden disease that is caused by an alteration of the genome that throughout childhood and during the early years of life. On results in complete loss, gain or disruption of the structural the other hand single gene diseases can pose a real medical integrity of a dosage sensitive gene(s) (Shaw and Lupski and health burden from the perinatal period to adult age 2004; Lupski and Stankiewicz 2005). Disruption in the with a peak around mid-childhood. In contrast, the poly- function of dosage sensitive gene may result from number genic/multifactorial diseases tend to present late, except for of mechanisms including gene interruption, gene fusion, developmental anomalies requiring active multi-disciplin- position effect, unmasking of a recessive allele, presence of ary care during early life. a functional polymorphism and gene transvection effect Recent advances in molecular genetics have enabled us (Fig. 1). Notable examples include a number of micro- to identify specific groups of disorders that result from deletion/duplication syndromes (Table 2). In these condi- characteristic mechanisms involving specific areas of the tions, there is a critical rearranged genomic segment human genome. Often these do not conform to the standard flanked by large (usually [10 kb), highly homologous low basic principles of genetics. A broad term ‘genomic dis- copy repeat [LCR] structures that can act as recombination orders’ has been coined to describe these conditions substrates. Meiotic recombination between non-allelic 123 Genomic Med. (2008) 2:69–76 71 disorders is distinct recognizable with distinguishing clin- ical and facial dysmorphic features (Fig. 2). Similarly, other chromosomal rearrangements (Table 3), including reciprocal, Robertsonian, and jumping translo- cations, inversions, isochromosomes, and small marker chromosomes,
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