Studies in Patients With Tuberous Sclerosis Complex
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|ClinicalTrials.gov Identifier: NCT03276195|
Recruitment Status : Recruiting
First Posted : September 8, 2017
Last Update Posted : March 10, 2020
|Condition or disease|
|Tuberous Sclerosis Complex|
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:
- To identify new gene mutations (genetic modifiers) in TSC familial pairs and sporadic cases that account for the phenotypic variability.
- Determination of quantitative differences in gene expression and allelic expression imbalance between mild and severe disease phenotype.
- 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.
|Study Type :||Observational|
|Estimated Enrollment :||1000 participants|
|Official Title:||Studies in Patients With Rett Syndrome, Tuberous Sclerosis Complex, Neurofibromatoses, and Other Neurodevelopmental Disorders|
|Study Start Date :||May 2016|
|Estimated Primary Completion Date :||December 2020|
|Estimated Study Completion Date :||December 2021|
Familial TSC and families
Individuals with familial TSC including those with a clinical diagnosis but no genetic confirmation and individuals with a genetic diagnosis
Sporadic TSC and families
Individuals with sporadic TSC including those with a clinical diagnosis but no genetic confirmation and individuals with a genetic diagnosis
- Next Generation Sequencing to Measure Phenotypic Variability [ Time Frame: Up to 4 Years ]Identify genetic variants and disease mechanisms responsible for phenotypic variability among patients who are diagnosed with Tuberous Sclerosis Complex (TSC) and their family members.
Biospecimen Retention: Samples With DNA
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03276195
|Contact: Keri Ramseyemail@example.com|
|United States, Arizona|
|Translational Genomics Research Institute (TGen)||Recruiting|
|Phoenix, Arizona, United States, 85004|
|Principal Investigator: Vinodh Narayanan, MD|
|Sub-Investigator: Sampathkumar Rangasamy, PhD|
|Sub-Investigator: Winnie Liang, PhD|
|Principal Investigator:||Vinodh Narayanan||Translational Genomics Research Institiute (TGen)|