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

Rory J Tinker1, Lisa Bastarache2, Kimberly Ezell1

  • 1Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

American Journal of Medical Genetics. Part A
|May 29, 2023
PubMed

Insights

Mosaic genetic disease (MGD) is a significant cause of genetic disorders, affecting over 4% of individuals. Parental mosaicism (PM) also contributes to presumed de novo variants (DNVs), highlighting the need for better MGD diagnosis.

Area of Science:

  • Genetics
  • Genomic Medicine
  • Clinical Diagnostics

Background:

  • Mosaicism, where an individual has cell populations with different genetic makeup, is understudied in diagnosed genetic diseases.
  • Presumed de novo variants (DNVs) in offspring are often assumed to originate newly, but parental mosaicism (PM) is an alternative explanation.
  • Understanding the prevalence and impact of mosaic genetic disease (MGD) and PM is crucial for accurate genetic diagnosis.

Purpose of the Study:

  • To determine the contribution of MGD and PM to genetic diseases and DNVs.
  • To investigate the prevalence of MGD in diagnosed probands and PM in parents of offspring with DNVs.
  • To characterize the phenotypic spectrum associated with MGD.

Main Methods:

  • Analysis of data from the Undiagnosed Diseases Network (UDN) cohort (N=1946).
  • Evaluation of electronic health records (EHR) from 12,472 individuals undergoing genetic testing.
  • Detection of mosaicism using chromosomal microarray and exome/genome sequencing.

Main Results:

  • MGD was diagnosed in 4.51% of UDN probands and in 6.03% (chromosomal microarray) and 2.99% (exome/genome sequencing) of EHR probands.
  • PM was identified in 2.86% of parents with offspring having DNVs in the UDN and in 2.34% of parents with presumed pathogenic DNVs in the EHR cohort.
  • Mosaicism was detected in 4.49% of all genetic tests performed, revealing a broad phenotypic spectrum of MGD.

Conclusions:

  • Mosaic genetic disease is a significant and heterogeneous contributor to diagnosed genetic disorders.
  • Parental mosaicism plays a role in the occurrence of presumed de novo variants, necessitating further investigation.
  • Improved diagnostic approaches for MGD and a deeper understanding of PM's contribution to DNV risk are required.
Keywords:
UDNmosaicismnext generation sequencingrare genetic disease

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