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

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.

• Authors: Krinio Giannikou, Kathryn D Lasseter, Joannes M Grevelink, Magdalena E Tyburczy, Kira A Dies, Zachary Zhu, Lana Hamieh, Bruce M Wollison, Aaron R Thorner, Stephen J Ruoss, Elizabeth A Thiele, Mustafa Sahin, David J Kwiatkowski
• Journal: Genetics in medicine : official journal of the American College of Medical Genetics (Genet Med) Vol. 21 Issue 11 Pg. 2639-2643 (11 2019) ISSN: 1530-0366 [Electronic] United States
• PMID: 31160751 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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