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Novel genomic techniques like DNA next-generation sequencing and advanced genotyping arrays open new avenues in the elucidation of genetic defects causing monogenic disorders. They not only speed up disease gene identification but enable one to systematically tackle previously intractable monogenic (Mendelian) disorders. These are mainly rare 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 coded protein. These mutations can be identified by whole exome sequencing, rendering whole genome sequencing necessary only in special cases.
Genotyping-arrays representing ~2x106 single-nucleotidepolymorphisms (SNP) allow highly accurate mapping of copy number variations (CNVs) and other genome structural variations often representing deletions readily detectable by exome sequencing. Based on these novel techniques we launched a project encompassing several medical centers to decipher the dozens of accumulated families with monogenic diseases. We currently focus mainly on neuronal disorders affecting the central nervous system, including mental retardation, microcephaly and congenital general anosmia (CGA) – an inborn complete loss of the sense of smell. These diseases are observed in various Israeli ethnic groups sometime due to high consanguineous marriages. In collaboration with the Duke Center for Human Genome Variation, we have implemented the most up-to-date sequencing and back-end analyses for sequence mapping, variation detection, and variation filtering. Based on the inheritance mode and family structure, we perform one of several modes of subgenome sequencing, including whole exome sequencing, chromosome X super-exome sequencing (including larger intronic territories and promoter regions), complete gene sequencing of linkage interval content, or system biology based gene groups. In preliminary results we have indicated the validity of our approach, identifying by whole exome sequencing the causative variation in at least one of the first group of 5 diseases studied. We aim at generating novel scientific insights related to the underlying biology of intellectual impairment disorders, as well as much better capacity to cope with genetic testing challenges. |
