CMT 1A: Disorders of the genome architecture: a review

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Genomic Med. 2009 Mar 11.

Disorders of the genome architecture: a review.

Kumar D.

Institute of Medical Genetics, Cardiff University, Cardiff, UK

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, -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.