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. 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.
|Clinical Study Identifier||NCT00341978|
|Sponsor||National Human Genome Research Institute (NHGRI)|
|Last Modified on||7 November 2020|
Select a piece of text and start making personal notes.
You have contacted , on
Your message has been sent to the study team at ,
Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.Learn more
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.Learn more
Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.Learn more
Congrats! You have your own personal workspace now.