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Article Dans Une Revue Human Mutation Année : 2011

Novel genomic techniques in the analysis of monogenic disorders

Julia Hullmann
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Silke Appenzeller
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Résumé

The molecular genetic cause of over 3000 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 e.g. 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 105 - 2x106 single-nucleotide-polymorphisms (SNP) and non-polymorphic 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 problem will is the differentiation between the many rare benign variants detected by novel genomic techniques and disease causing mutations.

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Dates et versions

hal-00612008 , version 1 (28-07-2011)

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Gregor Kuhlenbäumer, Julia Hullmann, Silke Appenzeller. Novel genomic techniques in the analysis of monogenic disorders. Human Mutation, 2011, 32 (2), pp.144. ⟨10.1002/humu.21400⟩. ⟨hal-00612008⟩

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