A Study of the Genetic Analysis of Brain Disorders
|First Received Date ICMJE||March 27, 2008|
|Last Updated Date||March 14, 2014|
|Start Date ICMJE||October 1998|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE||Not Provided|
|Original Primary Outcome Measures ICMJE||Not Provided|
|Change History||Complete list of historical versions of study NCT00645645 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE||Not Provided|
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||A Study of the Genetic Analysis of Brain Disorders|
|Official Title ICMJE||Genetic Analysis of Brain Disorders|
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.
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.
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 common genetic strategies including 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. 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.
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). 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.
|Study Type ICMJE||Observational|
|Study Design ICMJE||Not Provided|
|Target Follow-Up Duration||Not Provided|
|Sampling Method||Not Provided|
|Study Population||Not Provided|
|Condition ICMJE||Brain Disorders|
|Intervention ICMJE||Not Provided|
|Study Group/Cohort (s)||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE||6000|
|Completion Date||Not Provided|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
|Accepts Healthy Volunteers||No|
|Location Countries ICMJE||United States, Germany|
|NCT Number ICMJE||NCT00645645|
|Other Study ID Numbers ICMJE||980249, 98-HG-0249|
|Has Data Monitoring Committee||Not Provided|
|Responsible Party||Not Provided|
|Study Sponsor ICMJE||National Human Genome Research Institute (NHGRI)|
|Collaborators ICMJE||Not Provided|
|Information Provided By||National Institutes of Health Clinical Center (CC)|
|Verification Date||July 2013|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP