A multistep approach to the genotype-phenotype analysis of Polish patients with tuberous sclerosis complex

Eur J Med Genet. 2021 Oct;64(10):104309. doi: 10.1016/j.ejmg.2021.104309. Epub 2021 Aug 14.


The aim of this study was to evaluate a cost-effective diagnostic strategy for identification of casual variants for tuberous sclerosis complex (TSC) in the Polish population and to correlate the genetic results with selected phenotypic features. Fifty-five patients, aged 3-44 years, with a clinical diagnosis of TSC were enrolled into the study. All patients received a three-step analysis: next generation sequencing screening (NGS), multiplex ligation-dependent probe amplification (MLPA) and deep sequencing. This multistep approach obtained positive results in 51/55 (93%) patients: of the 51 positives TSC1 variants were observed in 16 (31%) and TSC2 variants in 35 (69%); these included 13 novel variants and two patients with mosaicism. Four patients (7%) had no mutation identified (NMI). Among the TSC1 gene variants, there were five nonsense, four frameshift, three large deletions, two missense and two splicing variants. For the TSC2 gene, 11 were missense, eight splicing, six frameshift, four large deletions, two in-frame deletions and four nonsense variants. The patients with TSC2 changes had their clinical diagnosis of TSC at a younger age than those with TSC1 changes (one year vs three years, p = 0.041). The TSC2 group demonstrated a higher number of major symptoms per patient (p = 0.04). Subependymal giant cell astrocytoma with concomitance of other brain lesions was more common in patients with missense mutations in either gene (23% vs 0%, p = 0.02). Such a multistep molecular diagnostic strategy could increase the possibility of detecting causal variants for TSC and may allow detection of mosaicism at low levels. Missense pathogenic variants in TSC1 or TSC2 gene might be associated with a higher risk of brain lesions.

Keywords: Genotype-phenotype correlation; Mosaicism; NGS; Novel pathogenic variants; Tuberous sclerosis complex.

MeSH terms

  • Adolescent
  • Adult
  • Brain / pathology
  • Child
  • Child, Preschool
  • Female
  • Gene Frequency
  • Genetic Testing / statistics & numerical data
  • Genotype*
  • Humans
  • Male
  • Mutation
  • Phenotype*
  • Poland
  • Tuberous Sclerosis / genetics*
  • Tuberous Sclerosis / pathology