Brain Disorders Clinical Trial
Official title:
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. 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.
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