Studies in Patients With Tuberous Sclerosis Complex

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

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.

Study Overview

• Status: Completed
• Conditions: 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
• Enrollment (Actual): 32

Contacts and Locations

• Study Contact: Name: Keri Ramsey; Phone Number: 602-687-8193; Email: kramsey@tgen.org

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85004
      • Translational Genomics Research Institute (TGen)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• 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.

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Family-Based
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Next Generation Sequencing to Measure Phenotypic Variability	Identify genetic variants and disease mechanisms responsible for phenotypic variability among patients who are diagnosed with Tuberous Sclerosis Complex (TSC) and their family members.	Up to 4 Years

Collaborators and Investigators

• Sponsor: Translational Genomics Research Institute
• Collaborators: United States Department of Defense
• Investigators: Principal Investigator: Vinodh Narayanan, Translational Genomics Research Institiute (TGen)

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2016
• Primary Completion (Actual): November 27, 2023
• Study Completion (Actual): November 27, 2023

Study Registration Dates

• First Submitted: April 28, 2017
• First Submitted That Met QC Criteria: September 5, 2017
• First Posted (Actual): September 8, 2017

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 27, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Genetics; Genomics; Neurodevelopmental Disorder
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Neoplasms; Congenital Abnormalities; Genetic Diseases, Inborn; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Neurocutaneous Syndromes; Hamartoma; Neoplasms, Multiple Primary; Sclerosis; Neurodevelopmental Disorders; Tuberous Sclerosis
• Other Study ID Numbers: vnarayanan15-016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing Time Frame: 6 months after completion of the study
• IPD Sharing Access Criteria: This data will be available to qualified researchers under controlled access