Journal article

Mosaic mutations in early-onset genetic diseases

Matt Halvorsen, Slave Petrovski, Renee Shellhaas, Yingying Tang, Laura Crandall, David Goldstein, Orrin Devinsky

GENETICS IN MEDICINE | NATURE PUBLISHING GROUP | Published : 2016

Abstract

PURPOSE: An emerging approach in medical genetics is to identify de novo mutations in patients with severe early-onset genetic disease that are absent in population controls and in the patient's parents. This approach, however, frequently misses post-zygotic "mosaic" mutations that are present in only a portion of the healthy parents' cells and are transmitted to offspring. METHODS: We constructed a mosaic transmission screen for variants that have an ~50% alternative allele ratio in the proband but are significantly less than 50% in the transmitting parent. We applied it to two family-based genetic disease cohorts consisting of 9 cases of sudden unexplained death in childhood (SUDC) and 338..

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University of Melbourne Researchers

Grants

Awarded by National Institute of Neurological Disorders and Stroke (the Epilepsy Phenome/Genome Project)


Awarded by Epi4K-Sequencing, Biostatistics and Bioinformatics Core


Awarded by NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE


Funding Acknowledgements

The authors are grateful for the participation of the affected families and researchers in the SUDC Registry and Research Collaborative, as well as the Epilepsy Phenome/Genome Project. The authors gratefully acknowledge the contributions of the following colleagues: Dawei Wang, Ann Poduri, Mark Hannibal, Michael Ackerman, and David Tester; Sergey Kisselev, Donna Dorshorst, and Prevention Genetics. This study was supported by grants from the National Institute of Neurological Disorders and Stroke (the Epilepsy Phenome/Genome Project (NS053998); Epi4K-Sequencing, Biostatistics and Bioinformatics Core (NS077303)), as well as funding from the Lange Shaw Family Foundation and Finding a Cure for Epilepsy and Seizures. The authors also thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison (http://exac.broadinstitute.org/about).