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Abstract: SA-PO819

Identifying Somatic Mosaicism for Tuberous Sclerosis Complex by Targeted Next-Generation Sequencing

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic


  • Carriazo Julio, Sol Maria, University Health Network, Toronto, Ontario, Canada
  • Ting, Ryan Robert Lee, University Health Network, Toronto, Ontario, Canada
  • Haghighi, Amirreza, University Health Network, Toronto, Ontario, Canada
  • Song, Xuewen, University Health Network, Toronto, Ontario, Canada
  • Paterson, Andrew, SickKids Research Institute, Toronto, Ontario, Canada
  • Pei, York P., University Health Network, Toronto, Ontario, Canada

Tuberous sclerosis complex (TSC) is a rare disease typically manifested with hamartomas affecting the skin, heart, brain, liver, and kidney. However, 15-20% of patients display mild clinical features suggestive but not diagnostic of TSC, and often they have no pathogenic TSC1 and TSC2 mutation detected (NMD). Here, we report our study of a cohort of patients with mild clinical features suspicious of TSC somatic mosaicism (SM) using Next Generation Sequencing (NGS).


We performed targeted gene panel screen by NGS using DNA samples from blood, buccal mucosa, and urinary epithelial cells (when available) and a minor allele frequency of 1% cut-off to detect mosaicism. Standard algorithms for sequence alignment, base calling, and QC filtering were applied to identify rare (MAF ≤1%) deleterious variants of high and moderate impact as predicted by multiple predictive algorithms. All potential pathogenic mosaic TSC1 and TSC2 variants were validated by a novel in-house assay (Mosaic Detection by Enrichment of Mutant Allele; MODEMA) or droplet digital PCR.


From a clinical review of 80 pts with confirmed or possible TSC, 18 patients with mild disease suspicious of TSC SM were sequenced. We found germline missense TSC1/TSC2 mutations in 5 patients, mosaic TSC1/TSC2 mutations in 9 patients in whom 7 were validated by MODEMA and/or digital PCR, and 4 with NMD. Patients with confirmed TSC SM were predominantly young female; all had multiple renal angiomyolipomas and few extra-renal clinical features.


Patients with mild clinical features suggestive but not diagnostic of TSC can be caused by missense or mosaic TSC1/TSC2 mutations. The diagnosis of TSC SM has important implications for genetic counselling and clinical prognostication, and can be improved by NGS.