Disorders of the genome architecture: a review

Dhavendra Kumar

doi:10.1007/s11568-009-9028-2

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.

Highlights

Developments in genetics and molecular biology have provided a vast amount of data and information to support the view that most human diseases have a significant genetic component
An understanding of the genetic basis of human disease has opened the way forward for a new taxonomy of human disease that will be free from limitations and bias in developing diagnostic criteria related to events which are often secondary and peripheral to its cause (Bell 2003)
Genetics may contribute to a new taxonomy of human disease for clinical practice

Summary

Introduction

Developments in genetics and molecular biology have provided a vast amount of data and information to support the view that most human diseases have a significant genetic component. It is widely believed that a clearer understanding of the mechanisms and pathways of a disease will assist us in delineating distinct disease subtypes, and may resolve many questions relating to variable disease symptoms, progression and response to therapy This might help in revising the current diagnostic criteria. Recent advances in molecular genetics have enabled us to identify specific groups of disorders that result from characteristic mechanisms involving specific areas of the human genome. Often these do not conform to the standard basic principles of genetics. The mechanisms involve certain genomic regions that directly or indirectly influence regulation and expression of one or more genes manifesting in complex phenotypes Some of these disorders are either listed as chromosomal or single-gene disorders

Phenotypes of disorders of genome architecture

AZFc microdeletion

Recombination substrates

Findings

Hunter syndrome