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Title: Mosaic mutations in early-onset genetic diseases.
Austin Authors: Halvorsen, Matt;Petrovski, Slavé;Shellhaas, Renée;Tang, Yingying;Crandall, Laura;Goldstein, David;Devinsky, Orrin
Affiliation: Department of Pathology, NYU Langone Medical Center, New York, New York, USA
SUDC Foundation, Herndon, Virginia, USA
Division of Pediatric Neurology, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan, USA
Department of Medicine, The University of Melbourne, Royal Melbourne Hospital, Melbourne, Victoria, Australia
Molecular Genetics Laboratory, New York City Office of the Chief Medical Examiner, New York, New York, USA
Institute for Genomic Medicine, Columbia University, New York, New York, USA
Comprehensive Epilepsy Center, Department of Neurology, NYU Langone Medical Center, New York, New York, USA
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Issue Date: Jul-2016 2015-12-30
Publication information: Genetics in medicine : official journal of the American College of Medical Genetics 2016; 18(7): 746-749
Abstract: 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. 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 previously published cases of epileptic encephalopathy. The screen identified six parental-mosaic transmissions across the two cohorts. The resultant rate of ~0.02 identified transmissions per trio is far lower than that of de novo mutations. Among these transmissions were two likely disease-causing mutations: an SCN1A mutation transmitted to an SUDC proband and her sibling with Dravet syndrome, as well as an SLC6A1 mutation in a proband with epileptic encephalopathy. These results highlight explicit screening for mosaic mutations as an important complement to the established approach of screening for de novo mutations.Genet Med 18 7, 746-749.
DOI: 10.1038/gim.2015.155
ORCID: 0000-0002-1527-961X
PubMed URL: 26716362
Type: Journal Article
Appears in Collections:Journal articles

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