Disorders of the genome architecture: a review.

IF 3.5 Q1 EDUCATION & EDUCATIONAL RESEARCH
Genomic medicine Pub Date : 2008-12-01 Epub Date: 2009-03-11 DOI:10.1007/s11568-009-9028-2
Dhavendra Kumar
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引用次数: 33

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.

基因组结构紊乱:综述。
遗传疾病是公认的人类疾病的主要类别之一。传统上,遗传疾病被细分为染色体(数字或结构畸变)、单基因或孟德尔疾病、多因素/多基因复杂疾病和线粒体遗传疾病。这些情况的很大一部分是偶然发生的。随着新分子技术的出现,一些新的疾病和畸形综合征被详细描述。其中一些条件不符合传统的继承模式,并且机制通常是复杂和独特的。例子包括亚微观微缺失或微重复、三核苷酸重复障碍、基因组印迹引起的表观遗传障碍、异常RNA模式引起的转录或翻译缺陷以及与单核苷酸多态性和拷贝数变异的致病关联。在这些明显的单基因疾病中,非等位基因同源重组与关键位点或基因簇两侧低拷贝数重复的存在有关。“基因组结构紊乱”一词也被用来强调这些疾病,例如Charcot-Marie-Tooth型IA、Smith-Magenis综合征、1型神经纤维瘤病以及其他许多具有指定OMIM编号的疾病。许多这些所谓的基因组疾病是零星发生的,主要是由非复发性从头基因组重排引起的。基因重排的位点特异性突变率似乎是碱基替换的核苷酸特异性突变率的两到四倍。最近对男性生殖细胞中几种与疾病相关的重组热点的研究表明,与微缺失综合征相比,过量的基因组重排导致了临床诊断不足的微重复。高分辨率基因组分析的广泛应用可以检测到由涉及从头拷贝数变异的基因组重排引起的更多散发性表型。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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