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Mosaicism and genetic disease

Jun. 22, 2023, 2:20 PM

by Leigh MacMillan

Mosaic genetic disease (MGD) is a condition in which the body’s cells do not all have the same genetic makeup — and a disease-causing genetic variant is only found in some of the cells. Little is known about the overall contribution of mosaicism to genetic disease. 

Rory Tinker, MD, and colleagues evaluated mosaicism in two cohorts with genetic disease: the Undiagnosed Diseases Network (UDN) and electronic health records (EHR) of individuals who underwent genetic testing at VUMC. 

They found MGD in 4.51% of UDN and 2.99% of EHR individuals with diagnosed genetic disease. For individuals with presumed de novo (not inherited) variants, they found parental mosaicism in the same variant in 2.86% of UDN and 2.34% of EHR cohorts. 

The findings, reported in the American Journal of Medical Genetics – Part A, show that mosaicism contributes significantly to genetic disease. Parental mosaicism may generate variants that are interpreted as de novo, and detecting such mosaicism could clarify recurrence risk for future children, the researchers note.

Co-authors of the study include Lisa Bastarache, MS, Kimberly Ezell, FNP, Shilpa Nadimpalli Kobren, PhD, Cecilia Esteves, MPH, Jill Rosenfeld, MS, CGC, Ellen Macnamara, MS, CGC, Rizwan Hamid, MD, PhD, Joy Cogan, PhD, David Rinker, PhD, Souhrid Mukharjee, Ian Glass, MD, Katrina Dipple, MD, PhD, John Phillips III, MD, and members of the Undiagnosed Diseases Network. The research was supported by National Institutes of Health grant HG007674. 

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