期刊
HUMAN MUTATION
卷 32, 期 2, 页码 144-151出版社
WILEY
DOI: 10.1002/humu.21400
关键词
monogenic; exome sequencing; disease gene identification
资金
- Deutsche Forschungsgemeinschaft (DFG)
- Innovative Medizinische Forschungsforderung'' of the University of Munster
- Intramurale Forschungsforderung'' of the University of Kiel
- Heinrich-Hertz-Foundation
- Association Francaise contre les Myopathies''
The molecular genetic cause of over 3,000 monogenic disorders is currently unknown. This review discusses how novel genomic techniques like Next-Generation DNA Sequencing (NGS) and genotyping arrays open new avenues in the elucidation of genetic defects causing monogenic disorders. They will not only speed up disease gene identification but will enable us to systematically tackle previously intractable monogenic disorders. These are mainly disorders not amenable to classic linkage analysis, for example, due to insufficient family size. Most monogenic diseases are caused by exonic mutations or splice-site mutations changing the amino acid sequence of the affected gene. These mutations can be identified by sequencing of all exons in the human genome (exome sequencing) rendering whole genome sequencing unnecessary in most cases. Genotyping arrays containing 10(5)-2 x 10(6) single nucleotide polymorphisms (SNPs) and nonpolymorphic markers allow highly accurate mapping of genomic deletions and duplications not detectable by exome sequencing, which are the second most common cause of monogenic disorders. However, several hundred rare, previously unknown sequence variants affecting the amino acid sequence of the encoded protein are found in the exome of every human individual. Therefore, the main challenge will be the differentiation between the many rare benign variants detected by novel genomic techniques and disease causing mutations. Hum Mutat 32:144-151, 2011. (C) 2011 Wiley-Liss, Inc.
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