Determining the pathogenicity of patient-derived TSC2 mutations by functional characterization and clinical evidence

Authors:
  • KDKayleigh M Dodd
    Kayleigh M Dodd
  • PDPeter A Davies
    Peter A Davies
  • NMNicole Martins
    Nicole Martins
  • HSHelen Stuart
    Helen Stuart
  • SMShane McKee
    Shane McKee
  • CKChris Kingswood
    Chris Kingswood
  • ASAnand Saggar
    Anand Saggar
  • ICIsabel Corderio
    Isabel Corderio
  • AMAna Maria Duarte Medeira
    Ana Maria Duarte Medeira
  • HKHelen Kingston
    Helen Kingston
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Abstract
Tuberous sclerosis complex (TSC) is a genetic condition characterized by the growth of benign tumours in multiple organs, including the brain and kidneys, alongside intellectual disability and seizures. Identification of a causative mutation in TSC1 or TSC2 is important for accurate genetic counselling in affected families, but it is not always clear from genetic data whether a sequence variant is pathogenic or not. In vitro functional analysis could provide support for determining whether an unclassified TSC1 or TSC2 variant is disease-causing. We have performed a detailed functional analysis of four patient-derived TSC2 mutations, E92V, R505Q, H597R and L1624P. One mutant, E92V, functioned similarly to wild-type TSC2, whereas H597R and L1624P had abnormal function in all assays, consistent with available clinical and segregation information. One TSC2 mutation, R505Q, was identified in a patient with intellectual disability, seizures and autistic spectrum disorder but who did not fulfil the diagnostic criteria for TSC. The R505Q mutation was also found in two relatives, one with mild learning difficulties and one without apparent phenotypic abnormality. R505Q TSC2 exhibited partially disrupted function in our assays. These data highlight the difficulties of assessing pathogenicity of a mutation and suggest that multiple lines of evidence, both genetic and functional, are required to assess the pathogenicity of some mutations.

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