Patient case: 14-year-old female with Li-Fraumeni syndrome; genetic feature: TP53

Clinical trial: Studies in Patients With Tuberous Sclerosis Complex

Summary: This study is aimed to carry out a systematic study to examine the effects of genetic variants (genetic modifiers) other than TSC genes on phenotypic variability in familial TSC patients (affected parent, child and unaffected siblings) and sporadic TSC.

Detailed description: Tuberous sclerosis complex (TSC) is an autosomal dominant neurogenetic disorder, caused by heterozygous mutations in at least two different genes, TSC1, and TSC2. It is estimated to affect 1 in 6000, and demonstrates both phenotypic and genetic heterogeneity. It is characterized by a variety of symptoms including skin lesions, renal angiomyolipomas, cardiac rhabdomyomas, seizures, and cognitive delay (mental retardation, autism, and behavior problems). The severity of the disease varies widely among patients with TSC in general, and variability in phenotype is detectable within single families, where all affected individuals have the same TSC1 or TSC2 mutation. Neurocognitive phenotypes in TSC vary from profound mental retardation, intractable epilepsy, and autism, to normal cognition and only a mild behavioral phenotype. However, the basis of this phenotypic variability is not understood. There is a growing body of literature implicating genetic variation in "modifier genes" as an agent for phenotypic heterogeneity in Mendelian disorders, such as TSC. The role of genetic modifiers on disease severity has not yet studied in familial TSC and sporadic TSC. This study is aimed to carry out a systematic study to examine the effects of genetic variants other than TSC genes on phenotypic variability in familial TSC patients (affected parent, child and unaffected siblings) and sporadic TSC. The main objectives of the study are:
  1. To identify new gene mutations (genetic modifiers) in TSC familial pairs and sporadic cases that account for the phenotypic variability.
  2. Determination of quantitative differences in gene expression and allelic expression imbalance between mild and severe disease phenotype.
  3. Establish a specimen repository of familial and sporadic TSC cohort to validate the genetic modifiers.
  To identify genetic variants that differentiate disease severity using next generation sequencing (NGS) in DNA, and gene expression profile in RNA from blood to identify disease-causing heterozygous TSC(1 or 2) mutation in parent-child (P-C) pairs and sporadic cases with a mild and severe form of the disease. Use of next-generation sequencing (NGS) along with improved data analysis in this proposal will overcome many of the barriers in identifying genetic modifiers. The investigators will also study cultured fibroblasts cells and buccal swabs from P-C pairs to validate the findings. Use of next-generation sequencing (NGS) along with improved data analysis in this proposal will overcome many of the barriers in identifying genetic modifiers. This research has the potential to address a critical scientific gap in understanding the phenotypic variability The investigators may be able to develop a "molecular profile" that correlates with and predicts disease severity. The findings may provide a tool for early prediction of disease severity, allowing for the use of disease modifying treatments that may prevent the development of a severe neurocognitive phenotype.
  As this is not a treatment protocol, there is no primary endpoint.

Eligibility: Inclusion Criteria:
  -  Diagnosis of familial TSC or sporadic TSC, or a biological relative of a person diagnosed with such a disorder.
  -  Willingness and ability to donate biospecimens to TGen for the purpose of propelling research. The minimum biospecimen donation capability is saliva and/or cheek swab. In most cases, blood or other tissue (skin biopsy) may be the ideal sample for study.
  Exclusion Criteria:
  -  Individuals that are 18 years or older that lack the capacity to consent for themselves.

Relevance to patient case: not relevant