Introduction:
Tuberous sclerosis is an autosomal dominant genetic disease caused by pathogenic TSC1 and TSC2 variants and characterised clinically by angiomyolipoma, and sometimes seizures, intellectual disability and kidney disease. Estimates of its population frequency vary from one in 2315 to one in 18,000 but angiomyolipomas occur in up to 2% of the population. The aim of this study was to determine a more accurate population frequency for Tuberous Sclerosis from the number of pathogenic variants in a normal population.
Methods:
TSC1 and TSC2 variants were downloaded from gnomAD v2.1.1 and annotated with ANNOVAR. The population frequency was calculated from the sum of pathogenic structural and null variants, and from rare missense changes classified disease-causing using computational tools. Population frequencies were also calculated from the number of gnomAD variants considered pathogenic in the ClinVar or LOVD databases which have used clinical data in their assessments.
Results:
Predicted pathogenic variants were found in TSC1 or TSC2 in one in 290 normal people using our assessment. They were commonest in people of African/African American ancestry and least common in Finns. Two founder variants were found in African Americans. Most changes were missense variants (307/408, 75%). The population frequency calculated from pathogenic variants in LOVD was one in 1296, and one in 4068 from ClinVar.
Conclusions:
The high proportion of pathogenic missense variants in this assessment was consistent with milder forms of the Tuberous sclerosis phenotype including renal angiomyolipoma in normal people. The deletions causing Tuberous sclerosis in LOVD and ClinVar are underestimated in this version of gnomAD which uses mainly WES for sequencing.
I have no potential conflict of interest to disclose.
I did not use generative AI and AI-assisted technologies in the writing process.