Low-level mosaicism in tuberous sclerosis complex: prevalence, clinical features, and risk of disease transmission

Genet Med. 2019 Nov;21(11):2639-2643. doi: 10.1038/s41436-019-0562-6. Epub 2019 Jun 4.

Abstract

Purpose: To examine the prevalence and spectrum of mosaic variant allele frequency (MVAF) in tuberous sclerosis complex (TSC) patients with low-level mosaicism and correlate genetic findings with clinical features and transmission risk.

Methods: Massively parallel sequencing was performed on 39 mosaic TSC patients with 170 different tissue samples.

Results: TSC mosaic patients (MVAF: 0-10%, median 1.7% in blood DNA) had a milder and distinct clinical phenotype in comparison with other TSC series, with similar facial angiofibromas (92%) and kidney angiomyolipomas (83%), and fewer seizures, cortical tubers, and multiple other manifestations (p < 0.0001 for six features). MVAF of TSC1/TSC2 pathogenic variants was highly variable in different tissue samples. Remarkably, skin lesions were the most reliable tissue for variant identification, and 6 of 39 (15%) patients showed no evidence of the variant in blood. Semen analysis showed absence of the variant in 3 of 5 mosaic men. The expected distribution of MVAF in comparison with that observed here suggests that there is a considerable number of individuals with low-level mosaicism for a TSC2 pathogenic variant who are not recognized clinically.

Conclusion: Our findings provide information on variability in MVAF and risk of transmission that has broad implications for other mosaic genetic disorders.

Keywords: TSC1; TSC2; mosaicism; transmission risk; tuberous sclerosis complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Disease Transmission, Infectious / statistics & numerical data
  • Female
  • Genotype
  • Humans
  • Male
  • Mosaicism
  • Mutation
  • Phenotype
  • Prevalence
  • Risk Factors
  • Tuberous Sclerosis / epidemiology*
  • Tuberous Sclerosis / genetics*
  • Tuberous Sclerosis Complex 1 Protein / genetics
  • Tuberous Sclerosis Complex 2 Protein / genetics
  • Tumor Suppressor Proteins / genetics
  • United States

Substances

  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins