Molecular Characterization of TSC1 and TSC2 Variants in a Greek Cohort of Tuberous Sclerosis Complex Patients.

Loss-of-function variants in TSC1 or TSC2 leading to mTOR pathway dysregulation and multisystem hamartoma formation.

The authors characterized the variant spectrum of TSC1 and TSC2 in 34 unrelated Greek probands, 26 with a definite tuberous sclerosis complex diagnosis and 8 with a possible diagnosis. Targeted next-generation sequencing of all coding exons and flanking exon-intron boundaries, with Sanger confirmation, identified pathogenic or likely pathogenic variants in 22 of 34 probands, an overall diagnostic yield of 65 %. Of these, 32 % (7/22) were in TSC1 and 68 % (15/22) in TSC2, and 7 of 22 variants (32 %) had not been reported previously. The molecular detection rate was 77 % (20/26) in patients meeting criteria for definite clinical diagnosis versus 25 % (2/8) in those with a possible diagnosis. Exploratory genotype-phenotype analysis showed a trend toward more severe clinical presentation in carriers of TSC2 variants.

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The most directly usable finding in clinic is not the variant spectrum itself but the yield contrast between definite (77 %) and possible (25 %) clinical diagnosis, which is what allows a family's expectations to be calibrated before testing. The trend toward greater severity with TSC2 remains exploratory across 22 carriers and should not be presented as an individual prognostic factor. The 12 negative probands underline the limits of a two-gene targeted strategy: mosaicism and deep intronic variants fall outside it, and WES/WGS with allelic coverage analysis remains the fallback.

Analysis by Dr Thibaut Benquey