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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 13, 2018
Sponsor:
Collaborator:
United States Department of Defense
Information provided by (Responsible Party):
Translational Genomics Research Institute

Brief 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.

Condition or disease
Tuberous Sclerosis Complex

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.


Study Type : Observational
Estimated Enrollment : 1000 participants
Observational Model: Family-Based
Time Perspective: Prospective
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 2019
Estimated Study Completion Date : December 2021


Group/Cohort
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



Primary Outcome Measures :
  1. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
This study will enroll subjects affected with Tuberous Sclerosis Complex (either familial or sporadic) and biological relatives (primarily the individual's parents or siblings). This study will consist of 1000 families who have an individual affected with TSC and wish to donate samples.
Criteria

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.

Information from the National Library of Medicine

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


Contacts
Contact: Keri Ramsey 602-687-8193 kramsey@tgen.org

Locations
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         
Sponsors and Collaborators
Translational Genomics Research Institute
United States Department of Defense
Investigators
Principal Investigator: Vinodh Narayanan Translational Genomics Research Institiute (TGen)

Responsible Party: Translational Genomics Research Institute
ClinicalTrials.gov Identifier: NCT03276195     History of Changes
Other Study ID Numbers: vnarayanan15-016
First Posted: September 8, 2017    Key Record Dates
Last Update Posted: March 13, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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.
Time Frame: 6 months after completion of the study
Access Criteria: This data will be available to qualified researchers under controlled access

Keywords provided by Translational Genomics Research Institute:
Neurodevelopmental Disorder
Genomics
Genetics

Additional relevant MeSH terms:
Sclerosis
Tuberous Sclerosis
Neurodevelopmental Disorders
Pathologic Processes
Hamartoma
Neoplasms
Neoplasms, Multiple Primary
Neoplastic Syndromes, Hereditary
Malformations of Cortical Development, Group I
Malformations of Cortical Development
Nervous System Malformations
Nervous System Diseases
Neurocutaneous Syndromes
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Congenital Abnormalities
Genetic Diseases, Inborn
Mental Disorders