title: Mosaic mutations in early-onset genetic diseases.
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.
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, New York, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Halvorsen
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, New York, USA.|Department of Medicine, The University of Melbourne, Austin Health and Royal Melbourne Hospital, Melbourne, Victoria, Australia.
authors.forename: Slavé
authors.initials: S
authors.lastname: Petrovski
authors.affiliation: Division of Pediatric Neurology, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Renée
authors.initials: R
authors.lastname: Shellhaas
authors.affiliation: Molecular Genetics Laboratory, New York City Office of the Chief Medical Examiner, New York, New York, USA.|Department of Pathology, NYU Langone Medical Center, New York, New York, USA.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Tang
authors.affiliation: SUDC Foundation, Herndon, Virginia, USA.|Comprehensive Epilepsy Center, Department of Neurology, NYU Langone Medical Center, New York, New York, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Crandall
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, New York, USA.
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
authors.affiliation: Comprehensive Epilepsy Center, Department of Neurology, NYU Langone Medical Center, New York, New York, USA.
authors.forename: Orrin
authors.initials: O
authors.lastname: Devinsky
mesh_terms: D017668:Age of Onset; D000483:Alleles; D053840:Brugada Syndrome / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D009030:Mosaicism; D009154:Mutation / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D010375:Pedigree; D035781:Siblings
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human