Mosaic mutations in early-onset genetic diseases

Genet Med. 2016 Jul;18(7):746-9. doi: 10.1038/gim.2015.155. Epub 2015 Dec 30.


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 previously published cases of epileptic encephalopathy.

Results: 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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Alleles
  • Brugada Syndrome / genetics*
  • Brugada Syndrome / mortality
  • Brugada Syndrome / pathology
  • Epilepsies, Myoclonic / genetics*
  • Epilepsies, Myoclonic / mortality
  • Epilepsies, Myoclonic / pathology
  • Female
  • Humans
  • Male
  • Mosaicism*
  • Mutation / genetics
  • NAV1.1 Voltage-Gated Sodium Channel / genetics*
  • Pedigree
  • Siblings


  • NAV1.1 Voltage-Gated Sodium Channel
  • SCN1A protein, human