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Genetic Analysis of Brain Disorders

The recruitment status of this study is unknown because the information has not been verified recently.
Verified September 2007 by National Institutes of Health Clinical Center (CC).
Recruitment status was  Recruiting
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00341978
First received: June 19, 2006
Last updated: March 3, 2008
Last verified: September 2007
  Purpose

A study of the complex genetics of brain development will be undertaken with an emphasis on those genes that cause the most common structural brain anomaly in humans called holoprosencephaly (HPE). This malformation of the brain can result from either environmental or genetic causes and it is the aim of these investigations to determine the genes responsible for both normal and abnormal brain development through the study of patients with this disorder. Mutations in one such gene, Sonic Hedgehog, have been shown by us to be responsible for approximately one quarter of familial cases of HPE. Other genes either related to the hedgehog pathway or located at unrelated defined genetic loci may also contribute to HPE and are the subject of active investigation. We anticipate that many genes important for normal brain development will be identified in the search for genetic causes of HPE.


Condition
Brain Disorders

Study Type: Observational
Official Title: Genetic Analysis of Brain Disorders

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Estimated Enrollment: 5000
Study Start Date: October 1998
Detailed Description:

Holoprosencephaly (HPE) covers a nearly continuous spectrum of midline abnormalities ranging from unmistakable cyclopia with absence of forebrain separation to mild microforms, such a single central incisor. Inder this research protocol, we deliberately keep the inclusion criteria as inclusive as possible to encompass the entire range of severity of the disorder.

The objective of these studies is to identify genetic factors that contribute to the pathogenesis of holoprosencephaly (HPE) or related brain malformations. Our approach involves the analysis of chromosomal rearrangements, use of positional cloning and gene isolation, and mutational analysis of candidate genes. All individuals with overt or subtle clinical findings consistent with the HPE spectrum are eligible to participate. Mutational analysis of our entire coded collection of HPE probands (approximately 600 cases) in selected genes is the principal research method used to determine that a given candidate gene is commonly mutated in HPE. We continuously re-evaluate the available mutational analysis methods in an effort to stay current with high-throughput technologies. Currently, we use denaturing high performance chromatography for initial mutation screens combined with sequencing. In the coming year(s) we may evaluate new technologies, such as high-resolution melting procedures, comparative genomic sequencing. Whenever a sequence variant is identified, that is not present in a commercially available control set of samples, attempts are made to test the functional significance of this change on the protein itself, or its expression. Sequence changes with a strong probability of being medically significant will be verified in a CLIA-approved lab (e.g. Muneke lab, for selected genes, or Gene Dx) at our expense, before any results are given to the family through genetic counseling. Parental DNA (and rarely that of siblings) is usually obtained at the same time that a proband is enrolled. Typically, these samples are studied only to perform limited family studies once a sequence variant of potential medical significance has already been determined. Linkage studies under this protocol are anticipated to be rare (ad hoc) studies and will proceed only following an independent evaluation that there is sufficient statistical power and strong likelihood of success. This research is best evaluated by our progress in the identification of genetic factors that contribute to normal and abnormal brain development.

The majority of subjects enrolled in this study will continue under the care of their local physician or genetic counselor with limited contact with the NIH investigators. Only rarely will families be seen at the NIH CC. These visits will involve face to face genetic counseling of medically significant results, following verification in a CLIA approved lab. This is not a treatment protocol. Our empiric ability to generate medically significant research results is limited by the extensive genetic and other etiologic heterogeneity. Therefore, for most participants this research is not a diagnostic study.

We have modified our procedures to test all new probands for mutations in the four HPE genes (SHH, ZIC2, SIX3 and TGIF) that are the best documented genes associated with HPE. Our lab is now certified to receive and test new samples according to CLIA guidelines. However, all previously collected samples will not be considered suitable for diagnostic purposes; hence, a second sample will need to be requested in these cases for CLIA confirmation.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

    1. This research is open to all participants with a known or suspected diagnosis of HPE or related brain malformations. Since the range of severity of HPE is extensive, we accept cases compatible with a wide HPE spectrum of findings. All races and genders are known to be at risk for HPE, anywhere in the world. Nationality or place of origin are not specific barriers to participation, provided that a blood tissue sample can be safely sent by international FedEx (to be billed to our account).
    2. Direct blood relatives (typically parents, and occasionally siblings of affected individuals) of patients with HPE are also eligible to participate.

EXCLUSION CRITERIA:

  1. Anyone unwilling to provide informed consent (for themselves as adults, or on behalf of their children as minors) or assent.
  2. Medical condition(s) or mental retardation are not in themselves reason for exclusion if in the judgement of the referring physician this would involve no more than minimal risk. We anticipate that children with mental handicaps would be included in the research population. We will make every effort to explain the study for the purpose of assent in a matter that the family feels is both age and developmentally appropriate for that child.
  3. We generally review a brief clinical description from the referring physician about a potential research subject to determine that the subject is appropriate to enter into the study. We reserve the right to exclude cases that are clearly not HPE or related to our direct research interests (e.g. HPE cases due to Trisomy 13 or 18 might not be considered directly related to current research). This almost never happens, and we would attempt to make referrals to a more appropriate investigator before a sample is sent to the NIH. Although not desirable, we will accept samples with a suspected diagnosis of HPE where this determination was made by the referring physician independent of any input from our HPE team. In such circumstances, we would likely verify by correspondence that a sample had been received and request further information.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00341978

Contacts
Contact: Maximilian Muenke, M.D. (301) 402-8167 mmuenke@nhgri.nih.gov

Locations
United States, Maryland
National Human Genome Research Institute (NHGRI), 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Germany
Children's Hospital of the University of Heidelberg, Germany Recruiting
Heidelberg, Germany
Sponsors and Collaborators
  More Information

No publications provided

ClinicalTrials.gov Identifier: NCT00341978     History of Changes
Other Study ID Numbers: 999998049, OH98-HG-N049
Study First Received: June 19, 2006
Last Updated: March 3, 2008
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Holoprosencephaly
Agenesis of Corpus
Callosum
Genetic Tests

Additional relevant MeSH terms:
Brain Diseases
Disease
Central Nervous System Diseases
Nervous System Diseases
Pathologic Processes

ClinicalTrials.gov processed this record on November 25, 2014