The use of next generation sequencing in rare disease

Titheradge, Hannah (2020). The use of next generation sequencing in rare disease. University of Birmingham. M.D.

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Introduction: High throughput next generation sequencing (NGS) strategies such as whole exome sequencing (WES) are frequently used in medical research to identify the molecular cause of Mendelian genetic disease. WES, or clinical exome sequencing strategies are now being adopted into clinical genetics practice. This study focuses on the application of WES for genetic diagnosis in a group of mainly consanguineous families with rare phenotypes for which an autosomal recessively inherited disease was suspected but the molecular basis was unknown.

Materials and methods: Families were recruited retrospectively from a previous research cohort (the National Autozygosity Mapping study) and prospectively from the Birmingham Women’s and Children’s NHS Foundation Trust. WES was subsequently performed.

Results: 35 families with rare genetic disorders were studied by WES (in 9 families a single individual underwent sequencing). After bioinformatics analysis of WES data and detailed reassessment of the phenotype a molecular genetic diagnosis was reached in 15 families (42.9%).

Conclusion: WES is an effective strategy for identifying the molecular basis of recessively inherited disorders in consanguineous families. The combination of WES with detailed phenotyping significantly improved variant interpretation and diagnostic yield over WES alone.

Type of Work: Thesis (Doctorates > M.D.)
Award Type: Doctorates > M.D.
Licence: All rights reserved
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Cancer and Genomic Sciences
Funders: Other
Other Funders: UCB Pharma
Subjects: R Medicine > R Medicine (General)


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