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Published on: October 18, 2013
Application of multiple mosaic callers improves post-zygotic mutation detection from exome sequencing data
Nandini G Sandran1, Dani L Fornarino1, Mark A Corbett1
1Neurogenetics Research Program, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia; Australian Collaborative Cerebral Palsy Research Group, Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia.
New pipelines accurately detect post-zygotic variants (PZVs) in parents and children, improving genetic diagnoses and recurrence risk estimates for monogenic disorders. This research enhances understanding of genetic variation in families.
Area of Science:
- Genetics
- Genomics
- Molecular Biology
Background:
- Post-zygotic variants (PZVs) are crucial for understanding genetic disorders but are challenging to identify.
- Current methods for PZV detection are not systematically applied to monogenic disorders.
- Accurate classification of de novo variants is essential for genetic diagnostics.
Purpose of the Study:
- To develop and validate pipelines for detecting PZVs in both parents (gonosomal mosaicism, pGoM) and children (somatic mosaicism, M3).
- To reclassify germline de novo variants as mosaic when appropriate.
- To assess the prevalence and impact of PZVs in large genetic datasets.
Main Methods:
- Applied PZV detection pipelines to exome sequencing data from the Australian Cerebral Palsy Biobank and Simons Simplex Collection.
- Validated candidate mosaic variants using deep amplicon sequencing or droplet digital PCR.
- Analyzed variant classification and reported novel PZVs.
Main Results:
- High validation rates for detected PZVs (up to 92.7% for pGoM, 69.2% for M3 trio).
- Significant proportion of individuals in the Australian Cerebral Palsy Biobank carried true-positive PZVs (16.6% probands, 20.7% parents).
- Reclassified 3.7% to 8.0% of germline de novo variants as mosaic, with many PZVs being previously unreported.
Conclusions:
- Existing approaches often misclassify or miss PZVs.
- Systematic application of developed pipelines can increase genetic diagnostic rates.
- Improved PZV detection aids in estimating recurrence risks and identifying novel disease genes.
