HoloprosencephalyNCT00645645
A Study of the Genetic Analysis of Brain Disorders
An observational study of Holoprosencephaly, run by National Human Genome Research Institute (NHGRI) at 1 site in United States.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 1 month and olderHealthy volunteers can take part
- Conditions the study is for
- Holoprosencephaly
- How many people
- 5,735 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Jun 2008to 19 Jan 2021
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 month and older
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: Patients with HPE.
Who may be able to join
- 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).
- Direct blood relatives (typically parents, and occasionally siblings of affected individuals) of patients with HPE are also eligible to participate.
- Pregnant women with a fetus with imaging evidence of holoprosencephaly. Most pregnancies affected by holoprosencephaly do not survive to term; therefore, pregnant women will be included in the study. DNA obtained from pregnant women (amniocytes and blood) will be analyzed for genetic etiologies. This will allow for recurrence risk assessment and genetic counseling.
Who cannot join
- Anyone unwilling to provide informed consent (for themselves as adults, or on behalf of their children as minors) or assent.
- Medical condition(s) or cognitive impairment 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.
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
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.
Read the 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.
The objective of these studies is to identify genetic factors (coding and non-coding) 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. This approach pertains to an individual gene(s) or genetic element(s) as well as to targeted capture panels that study gene sets of hundreds of developmental genes whose involvement in brain development is supported by the basic research literature. We are also asking to include the option of investigating the entire set of genetic factors present in the DNA or RNA of patients who have HPE through a proposed change in the consent documents. 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 commercial lab) 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. Participation by direct blood relatives is encouraged since virtually all bone fide mutations are either family-specific or de novo. Such family information is critical for the research determination of genetic risk factors and accurate genetic counseling.
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). As new genetic elements that confer a risk for HPE are identified, we intend to add additional tests to this panel. 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.
- Conditions
- Holoprosencephaly
- Keywords
- Holoprosencephaly, Agenesis of Corpus, Callosum, Genetic Tests
- Medical subject headings
- Holoprosencephaly
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| holoprosencephaly (HPE) | individuals with overt or subtle clinical findings consistent with the HPE spectrum are eligible to participate |
What is being measured
The primary outcome is the main question the study is designed to answer.
natural history
The objectives of this study are primarily to increase our understanding of the genetic causes of brain malformations.
Measured: lifetime/ongoing
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Mar 2008 (estimated)
- Study start1 Jun 2008
- Primary completion19 Jan 2021
- Study completion19 Jan 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for HoloprosencephalyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 5,735 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Human Genome Research Institute (NHGRI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Benjamin D Solomon, M.D., Principal investigator, National Human Genome Research Institute (NHGRI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00645645
- Sponsor's protocol ID
- 980249
- Other IDs
- 98-HG-0249
- Status last verified
- Dec 2021
- First submitted
- 27 Mar 2008
- Last updated
- 14 Dec 2021
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Belloni E, Muenke M, Roessler E, Traverso G, Siegel-Bartelt J, Frumkin A, Mitchell HF, Donis-Keller H, Helms C, Hing AV, Heng HH, Koop B, Martindale D, Rommens JM, Tsui LC, Scherer SW. Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nat Genet. 1996 Nov;14(3):353-6. doi: 10.1038/ng1196-353.
PubMed 8896571Cohen MM Jr. Perspectives on holoprosencephaly: Part I. Epidemiology, genetics, and syndromology. Teratology. 1989 Sep;40(3):211-35. doi: 10.1002/tera.1420400304.
PubMed 2688166Cohen MM Jr, Sulik KK. Perspectives on holoprosencephaly: Part II. Central nervous system, craniofacial anatomy, syndrome commentary, diagnostic approach, and experimental studies. J Craniofac Genet Dev Biol. 1992 Oct-Dec;12(4):196-244.
PubMed 1494025
Study at a glance
From the registry record, last updated by the sponsor on 14 Dec 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Genetic Analysis of Brain Disorders
- ClinicalTrials.gov ID
- NCT00645645
- Acronym / sponsor ID
- 980249
- Conditions
- Holoprosencephaly
- Keywords
- Holoprosencephaly, Agenesis of Corpus, Callosum, Genetic Tests
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 5,735 participants (actual)
- Lead sponsor
- National Human Genome Research Institute (NHGRI)US National Institutes of Health
- Study start
- 1 Jun 2008 (actual)
- Primary completion
- 19 Jan 2021 (actual)
- Study completion
- 19 Jan 2021 (actual)
- First posted
- 28 Mar 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
The objective of these studies is to identify genetic factors (coding and non-coding) 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. This approach pertains to an individual gene(s) or genetic element(s) as well as to targeted capture panels that study gene sets of hundreds of developmental genes whose involvement in brain development is supported by the basic research literature. We are also asking to include the option of investigating the entire set of genetic factors present in the DNA or RNA of patients who have HPE through a proposed change in the consent documents. 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 commercial lab) 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. Participation by direct blood relatives is encouraged since virtually all bone fide mutations are either family-specific or de novo. Such family information is critical for the research determination of genetic risk factors and accurate genetic counseling.
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). As new genetic elements that confer a risk for HPE are identified, we intend to add additional tests to this panel. 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 design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| holoprosencephaly (HPE) | – | –individuals with overt or subtle clinical findings consistent with the HPE spectrum are eligible to participate |
Who may qualify
- Ages
- 1 month and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Patients with HPE.
Key inclusion criteria (3 listed)
Key exclusion criteria (3 listed)
- Anyone unwilling to provide informed consent (for themselves as adults, or on behalf of their children as minors) or assent.
- Medical condition(s) or cognitive impairment 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.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
natural history
Time frame: lifetime/ongoing
The objectives of this study are primarily to increase our understanding of the genetic causes of brain malformations.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Dec 2021.
- Background: PubMed 8896571Belloni E, Muenke M, Roessler E, Traverso G, Siegel-Bartelt J, Frumkin A, Mitchell HF, Donis-Keller H, Helms C, Hing AV, Heng HH, Koop B, Martindale D, Rommens JM, Tsui LC, Scherer SW. Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nat Genet. 1996 Nov;14(3):353-6. doi: 10.1038/ng1196-353.
- Background: PubMed 2688166Cohen MM Jr. Perspectives on holoprosencephaly: Part I. Epidemiology, genetics, and syndromology. Teratology. 1989 Sep;40(3):211-35. doi: 10.1002/tera.1420400304.
- Background: PubMed 1494025Cohen MM Jr, Sulik KK. Perspectives on holoprosencephaly: Part II. Central nervous system, craniofacial anatomy, syndrome commentary, diagnostic approach, and experimental studies. J Craniofac Genet Dev Biol. 1992 Oct-Dec;12(4):196-244.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Benjamin D Solomon, M.D. principal investigator
National Human Genome Research Institute (NHGRI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Holoprosencephaly, run by National Human Genome Research Institute (NHGRI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Dec 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
natural history (time frame: lifetime/ongoing). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00645645, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Dec 2021.