Exome sequencing analysis of rare autosomal recessive disorders

[摘要] Since the human genome project was completed in 2003, extraordinary progress has been made in the field of genomics with the development of new sequencing technologies and the widespread introduction of next generation sequencing (NGS). The application of NGS initiated a new era in genomics by massively increasing the number and diversity of the sequenced genomes at lower cost. Human Molecular Genetics has greatly benefited from the use of NGS-based strategies to identify human disease genes. In this thesis, I investigated the application of genetic techniques to investigate the molecular basis of autosomal recessively inherited disorders of unknown etiology. A range of disease phenotypes, including oligodontia and fetal akinesia/multiple pterygium syndrome (FA/MPS), were investigated in patient cohorts that included many cases with parental consanguinity. Using an autozygosity linkage analysis-based approach and Sanger sequencing of candidate genes resulted in the identification germline RYR1 mutations in FA/MPS. Subsequently, using exome sequencing techniques, the molecular basis of FA/MPS was further elucidated by the identification of germline mutations in RYR1, NEB, CHRNG, CHRNA1 and TPM2. The application of NGS in genetically heterogeneous disorders such as fetal akinesia/multiple pterygium syndrome can enable better and less expensive molecular diagnostic services aimed at specific mutation spectra, though more extensive sequencing can lead to the identification of larger numbers of variants of uncertain significance.

[发布机构] University:University of Birmingham;Department:Institute of Biomedical Research

[关键词] Q Science;QH Natural history;QH301 Biology