<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03276195</url>
  </required_header>
  <id_info>
    <org_study_id>vnarayanan15-016</org_study_id>
    <nct_id>NCT03276195</nct_id>
  </id_info>
  <brief_title>Studies in Patients With Tuberous Sclerosis Complex</brief_title>
  <official_title>Studies in Patients With Rett Syndrome, Tuberous Sclerosis Complex, Neurofibromatoses, and Other Neurodevelopmental Disorders</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Translational Genomics Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>United States Department of Defense</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
  </sponsors>
  <source>Translational Genomics Research Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is aimed to carry out a systematic study to examine the effects of genetic&#xD;
      variants (genetic modifiers) other than TSC genes on phenotypic variability in familial TSC&#xD;
      patients (affected parent, child and unaffected siblings) and sporadic TSC.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Tuberous sclerosis complex (TSC) is an autosomal dominant neurogenetic disorder, caused by&#xD;
      heterozygous mutations in at least two different genes, TSC1, and TSC2. It is estimated to&#xD;
      affect 1 in 6000, and demonstrates both phenotypic and genetic heterogeneity. It is&#xD;
      characterized by a variety of symptoms including skin lesions, renal angiomyolipomas, cardiac&#xD;
      rhabdomyomas, seizures, and cognitive delay (mental retardation, autism, and behavior&#xD;
      problems). The severity of the disease varies widely among patients with TSC in general, and&#xD;
      variability in phenotype is detectable within single families, where all affected individuals&#xD;
      have the same TSC1 or TSC2 mutation. Neurocognitive phenotypes in TSC vary from profound&#xD;
      mental retardation, intractable epilepsy, and autism, to normal cognition and only a mild&#xD;
      behavioral phenotype. However, the basis of this phenotypic variability is not understood.&#xD;
      There is a growing body of literature implicating genetic variation in &quot;modifier genes&quot; as an&#xD;
      agent for phenotypic heterogeneity in Mendelian disorders, such as TSC. The role of genetic&#xD;
      modifiers on disease severity has not yet studied in familial TSC and sporadic TSC. This&#xD;
      study is aimed to carry out a systematic study to examine the effects of genetic variants&#xD;
      other than TSC genes on phenotypic variability in familial TSC patients (affected parent,&#xD;
      child and unaffected siblings) and sporadic TSC. The main objectives of the study are:&#xD;
&#xD;
        1. To identify new gene mutations (genetic modifiers) in TSC familial pairs and sporadic&#xD;
           cases that account for the phenotypic variability.&#xD;
&#xD;
        2. Determination of quantitative differences in gene expression and allelic expression&#xD;
           imbalance between mild and severe disease phenotype.&#xD;
&#xD;
        3. Establish a specimen repository of familial and sporadic TSC cohort to validate the&#xD;
           genetic modifiers.&#xD;
&#xD;
      To identify genetic variants that differentiate disease severity using next generation&#xD;
      sequencing (NGS) in DNA, and gene expression profile in RNA from blood to identify&#xD;
      disease-causing heterozygous TSC(1 or 2) mutation in parent-child (P-C) pairs and sporadic&#xD;
      cases with a mild and severe form of the disease. Use of next-generation sequencing (NGS)&#xD;
      along with improved data analysis in this proposal will overcome many of the barriers in&#xD;
      identifying genetic modifiers. The investigators will also study cultured fibroblasts cells&#xD;
      and buccal swabs from P-C pairs to validate the findings. Use of next-generation sequencing&#xD;
      (NGS) along with improved data analysis in this proposal will overcome many of the barriers&#xD;
      in identifying genetic modifiers. This research has the potential to address a critical&#xD;
      scientific gap in understanding the phenotypic variability The investigators may be able to&#xD;
      develop a &quot;molecular profile&quot; that correlates with and predicts disease severity. The&#xD;
      findings may provide a tool for early prediction of disease severity, allowing for the use of&#xD;
      disease modifying treatments that may prevent the development of a severe neurocognitive&#xD;
      phenotype.&#xD;
&#xD;
      As this is not a treatment protocol, there is no primary endpoint.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date>May 2016</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Family-Based</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Next Generation Sequencing to Measure Phenotypic Variability</measure>
    <time_frame>Up to 4 Years</time_frame>
    <description>Identify genetic variants and disease mechanisms responsible for phenotypic variability among patients who are diagnosed with Tuberous Sclerosis Complex (TSC) and their family members.</description>
  </primary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">1000</enrollment>
  <condition>Tuberous Sclerosis Complex</condition>
  <arm_group>
    <arm_group_label>Familial TSC and families</arm_group_label>
    <description>Individuals with familial TSC including those with a clinical diagnosis but no genetic confirmation and individuals with a genetic diagnosis</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sporadic TSC and families</arm_group_label>
    <description>Individuals with sporadic TSC including those with a clinical diagnosis but no genetic confirmation and individuals with a genetic diagnosis</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Participant samples for this study may include blood, urine or saliva. An optional skin&#xD;
      biopsy may also be collected. Additional samples (such as cerebrospinal fluid, muscle&#xD;
      biopsies, and brain tissue) can be used when they are collected as part of a clinically&#xD;
      indicated procedure.&#xD;
&#xD;
      Where possible, parents of a child will be enrolled to identify genetic variants (genetic&#xD;
      modifiers). These and other biological relatives will be asked to donate blood samples and&#xD;
      optional skin biopsy samples for study participation. If the relative is unable to donate a&#xD;
      blood sample, a saliva sample can be collected instead.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        This study will enroll subjects affected with Tuberous Sclerosis Complex (either familial&#xD;
        or sporadic) and biological relatives (primarily the individual's parents or siblings).&#xD;
        This study will consist of 1000 families who have an individual affected with TSC and wish&#xD;
        to donate samples.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of familial TSC or sporadic TSC, or a biological relative of a person&#xD;
             diagnosed with such a disorder.&#xD;
&#xD;
          -  Willingness and ability to donate biospecimens to TGen for the purpose of propelling&#xD;
             research. The minimum biospecimen donation capability is saliva and/or cheek swab. In&#xD;
             most cases, blood or other tissue (skin biopsy) may be the ideal sample for study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Individuals that are 18 years or older that lack the capacity to consent for&#xD;
             themselves.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Vinodh Narayanan</last_name>
    <role>Principal Investigator</role>
    <affiliation>Translational Genomics Research Institiute (TGen)</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Keri Ramsey</last_name>
    <phone>602-687-8193</phone>
    <email>kramsey@tgen.org</email>
  </overall_contact>
  <location>
    <facility>
      <name>Translational Genomics Research Institute (TGen)</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85004</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Vinodh Narayanan, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Sampathkumar Rangasamy, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Winnie Liang, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>April 28, 2017</study_first_submitted>
  <study_first_submitted_qc>September 5, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 8, 2017</study_first_posted>
  <last_update_submitted>October 18, 2022</last_update_submitted>
  <last_update_submitted_qc>October 18, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 19, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Neurodevelopmental Disorder</keyword>
  <keyword>Genomics</keyword>
  <keyword>Genetics</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberous Sclerosis</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
    <mesh_term>Neurodevelopmental Disorders</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_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_description>
    <ipd_time_frame>6 months after completion of the study</ipd_time_frame>
    <ipd_access_criteria>This data will be available to qualified researchers under controlled access</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03276195
org study id: vnarayanan15-016
nct id: NCT03276195
lead sponsor: 
collaborator: 
has dmc: Yes
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.
observational model: Family-Based
time perspective: Prospective
measure: Next Generation Sequencing to Measure Phenotypic Variability
time frame: Up to 4 Years
description: Identify genetic variants and disease mechanisms responsible for phenotypic variability among patients who are diagnosed with Tuberous Sclerosis Complex (TSC) and their family members.
arm group label: Familial TSC and families
description: Individuals with familial TSC including those with a clinical diagnosis but no genetic confirmation and individuals with a genetic diagnosis
arm group label: Sporadic TSC and families
description: Individuals with sporadic TSC including those with a clinical diagnosis but no genetic confirmation and individuals with a genetic diagnosis
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.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Vinodh Narayanan
role: Principal Investigator
affiliation: Translational Genomics Research Institiute (TGen)
last name: Keri Ramsey
phone: 602-687-8193
email: kramsey@tgen.org
facility: 
status: Recruiting
investigator: 
investigator: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Tuberous Sclerosis
mesh term: Sclerosis
mesh term: Neurodevelopmental Disorders
sharing ipd: Yes
ipd 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 time frame: 6 months after completion of the study
ipd access criteria: This data will be available to qualified researchers under controlled access