Phenotypic distinctions between mosaic forms of tuberous sclerosis complex.

Area of Science:

• Genetics
• Dermatology
• Medical Genetics

Background:

• Tuberous sclerosis complex (TSC) is a genetic disorder.
• Mosaic TSC involves variants in TSC1 or TSC2 genes.
• Understanding mosaic TSC subtypes is crucial for prognosis.

Purpose of the Study:

• To determine if mosaic TSC can be stratified into subtypes.
• To correlate subtypes with disease prognosis and extent.
• To investigate the relationship between variant allele fraction (VAF) and disease severity.

Main Methods:

• Next-generation sequencing of skin and other samples to identify mosaic pathogenic variants in TSC1 or TSC2.
• Retrospective analysis of patient records for disease extent, onset age, and family history.
• Correlation analysis of VAF, clinical findings, and disease characteristics.

Main Results:

• Mosaic TSC patients with asymmetric facial angiofibromas had fewer findings (median 4) and later onset (median 24 years) compared to those with symmetric angiofibromas (8 findings, 10 years) and germline TSC (10 findings, 4 years).
• Cutaneous and internal organ involvement positively correlated in mosaic TSC (R=0.62, p=0.005).
• Blood VAF positively correlated with the number of major features (R=0.55, p=0.028).

Conclusions:

• Mosaic TSC phenotypes range from mild to severe, sometimes indistinguishable from germline TSC.
• Asymmetric facial angiofibromas in mosaic TSC are associated with fewer disease findings, later onset, and lower blood VAF.
• Stratification of mosaic TSC based on facial angiofibroma distribution may aid in predicting prognosis.