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Ultra-long Read Sequencing for Whole Genomic DNA Analysis
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Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and
Alba Sanchis-Juan1,2, Jonathan Stephens1,2, Courtney E French3
1Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge, CB2 0PT, UK.
Genome Medicine
|December 12, 2018
Summary
Complex structural variants (cxSVs) are identified as a cause of Mendelian disease. Analyzing breakpoints reveals their formation mechanisms, aiding clinical diagnosis of rare genetic disorders.
Area of Science:
- Genomics
- Human Genetics
- Molecular Biology
Background:
- Complex structural variants (cxSVs) are significant contributors to human genomic variation.
- cxSVs have been implicated as a cause of Mendelian diseases.
Purpose of the Study:
- To identify cxSVs associated with Mendelian disease using short-read whole-genome sequencing (WGS).
- To precisely determine the configuration of these variants.
- To investigate the mechanisms underlying cxSV formation.
Main Methods:
- Performed short-read WGS on 1324 undiagnosed rare disease patients.
- Analyzed breakpoint junctions to identify cxSVs.
- Utilized long-read WGS and gene expression analysis for detailed case resolution.
Main Results:
- Identified three pathogenic cxSVs: affecting ARID1B, HNRNPU, and CEP78.
- Resolved a complex cxSV overlapping CDKL5 using long-read WGS, showing both disrupted and intact copies.
- Breakpoint analysis indicated involvement of microhomology and repetitive elements in cxSV formation.
Conclusions:
- cxSVs are confirmed as a cause of Mendelian disease, warranting clinical consideration.
- Precise breakpoint resolution is crucial for interpreting cxSV pathogenicity.
- Evidence suggests replication-based mechanisms contribute to cxSV formation.
Keywords:
ARID1BCDKL5CEP78Complex structural variantGenome sequencingHNRNPUNanoporeNext-generation sequencingMore Related Videos
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