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Tuberous Sclerosis Complex

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Individuals with familial TSC including those with a clinical diagnosis but no genetic confirmation and individuals with a genetic diagnosis

Individuals with sporadic TSC including those with a clinical diagnosis but no genetic confirmation and individuals with a genetic diagnosis

Vinodh Narayanan

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.

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.

Participant samples for this study may include blood, urine or saliva. An optional skin biopsy may also be collected. Additional samples (such as cerebrospinal fluid, muscle biopsies, and brain tissue) can be used when they are collected as part of a clinically indicated procedure.

Where possible, parents of a child will be enrolled to identify genetic variants (genetic modifiers). These and other biological relatives will be asked to donate blood samples and optional skin biopsy samples for study participation. If the relative is unable to donate a blood sample, a saliva sample can be collected instead.

Studies in Patients With Tuberous Sclerosis Complex

Studies in Patients With Rett Syndrome, Tuberous Sclerosis Complex, Neurofibromatoses, and Other Neurodevelopmental Disorders

De-identified participant study data will be published to a central data repository that allows qualified research scientists to access and look at the data under controlled access.

Identify genetic variants and disease mechanisms responsible for phenotypic variability among patients who are diagnosed with Tuberous Sclerosis Complex (TSC) and their family members.

United States Department of Defense

Translational Genomics Research Institute

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Studies in Patients With Tuberous Sclerosis Complex	NCT03276195	Tuberous Sclero...		-	Translational Genomics Research Institute
Studies in Patients With Tuberous Sclerosis Complex	NCT03276195	Tuberous Sclero...		-	Translational Genomics Research Institute

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