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. 2023 Oct;191(10):2482-2492.
doi: 10.1002/ajmg.a.63309. Epub 2023 May 29.

The contribution of mosaicism to genetic diseases and de novo pathogenic variants

Rory J Tinker  1 , Lisa Bastarache  2 , Kimberly Ezell  1 , Shilpa Nadimpalli Kobren  3 , Cecilia Esteves  3 , Jill A Rosenfeld  4 , Ellen F Macnamara  5 , Rizwan Hamid  1 , Joy D Cogan  1 , David Rinker  6 , Souhrid Mukharjee  6 , Ian Glass  7 , Katrina Dipple  7 , John A Phillips 3rd  1 ; Undiagnosed Diseases Network
Affiliations

The contribution of mosaicism to genetic diseases and de novo pathogenic variants

Rory J Tinker et al. Am J Med Genet A. 2023 Oct.

Abstract

The contribution of mosaicism to diagnosed genetic disease and presumed de novo variants (DNV) is under investigated. We determined the contribution of mosaic genetic disease (MGD) and diagnosed parental mosaicism (PM) in parents of offspring with reported DNV (in the same variant) in the (1) Undiagnosed Diseases Network (UDN) (N = 1946) and (2) in 12,472 individuals electronic health records (EHR) who underwent genetic testing at an academic medical center. In the UDN, we found 4.51% of diagnosed probands had MGD, and 2.86% of parents of those with DNV exhibited PM. In the EHR, we found 6.03% and 2.99% and (of diagnosed probands) had MGD detected on chromosomal microarray and exome/genome sequencing, respectively. We found 2.34% (of those with a presumed pathogenic DNV) had a parent with PM for the variant. We detected mosaicism (regardless of pathogenicity) in 4.49% of genetic tests performed. We found a broad phenotypic spectrum of MGD with previously unknown phenotypic phenomena. MGD is highly heterogeneous and provides a significant contribution to genetic diseases. Further work is required to improve the diagnosis of MGD and investigate how PM contributes to DNV risk.

Keywords: UDN; mosaicism; next generation sequencing; rare genetic disease.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

The department of Molecular & Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories. There are no over conflict of interests to declare.

Figures

FIGURE 1
FIGURE 1
A graphical representation of the subgroups analyzed in our study. (a) UDN diagnoses, (b) Mosaic variants identified in the VEHR, (c) VEHR Diagnoses and (d) presumed de novo variants found to originate from parental mosaicism in both the UDN and VEHR. CMA, chromosomal microarray analysis; UDN, undiagnosed disease network; VEHR, Vanderbilt electronic healthcare record.
See this image and copyright information in PMC

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