Uncovering hidden genetic variations: long-read sequencing reveals new insights into tuberous sclerosis complex.

BACKGROUND

Tuberous sclerosis is a multi-system disorder caused by mutations in either or . The majority of affected patients (85%-90%) have heterozygous variants, and a smaller number (around 5%) have mosaic variants. Despite using various techniques, some patients still have "no mutation identified" (NMI).

METHODS

We hypothesized that the causal variants of patients with NMI may be structural variants or deep intronic variants. To investigate this, we sequenced the DNA of 26 tuberous sclerosis patients with NMI using targeted long-read sequencing.

RESULTS

We identified likely pathogenic/pathogenic variants in 13 of the cases, of which 6 were large deletions, four were InDels, two were deep intronic variants, one had retrotransposon insertion in either or , and one was complex rearrangement. Furthermore, there was a Alu element insertion with a high suspicion of pathogenicity that was classified as a variant of unknown significance.

CONCLUSION

Our findings expand the current knowledge of known pathogenic variants related to tuberous sclerosis, particularly uncovering mosaic complex structural variations and retrotransposon insertions that have not been previously reported in tuberous sclerosis. Our findings suggest a higher prevalence of mosaicism among tuberous sclerosis patients than previously recognized. Our results indicate that long-read sequencing is a valuable approach for tuberous sclerosis cases with no mutation identified (NMI).