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

Mosaic mutations in early-onset genetic diseases.

Author information

1
Institute for Genomic Medicine, Columbia University, New York, New York, USA.
2
Department of Medicine, The University of Melbourne, Austin Health and Royal Melbourne Hospital, Melbourne, Victoria, Australia.
3
Division of Pediatric Neurology, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan, USA.
4
Molecular Genetics Laboratory, New York City Office of the Chief Medical Examiner, New York, New York, USA.
5
Department of Pathology, NYU Langone Medical Center, New York, New York, USA.
6
SUDC Foundation, Herndon, Virginia, USA.
7
Comprehensive Epilepsy Center, Department of Neurology, NYU Langone Medical Center, New York, New York, USA.

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 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.

PMID:
26716362
PMCID:
PMC4929028
DOI:
10.1038/gim.2015.155
[Indexed for MEDLINE]
Free PMC Article

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