- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00478712
Hirschsprung Disease Genetic Study
Genetic Analysis of Hirschsprung Disease
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Hirschsprung disease (HSCR) is a birth defect resulting from the absence of nerve (ganglion) cells in the gastrointestinal tract. Hirschsprung disease has a population incidence of 1/5000 live births and most often occurs as an isolated condition. However, approximately 30% of HSCR cases are associated with other birth defects such as Down syndrome, deafness, hypopigmentation, and congenital central hypoventilation syndrome. Hirschsprung disease is a genetic condition with autosomal dominant, autosomal recessive, and multigenic patterns of inheritance described.
Dr. Aravinda Chakravarti's laboratory has been investigating the genetics of Hirschsprung disease (HSCR) for more than twenty five years. The goal of this research study is to identify genes harboring causative HSCR mutations and to better understand the complex inheritance of HSCR in families by whole genome mapping and sequencing studies. Specifically, the study aims to determine the frequency with which mutations in any human gene lead to familial and isolated forms of HSCR. Further, the study will collect clinical information and investigate possible genotype - phenotype correlations.
Molecular analysis using markers and sequencing, and statistical analysis of these data will be used to identify regions of human chromosomes where putative HSCR disease genes may be located. In addition, the DNA sequence of known and/or suspected HSCR genes will be assessed in individual patients and their family members, in search of causative HSCR susceptibility variants and variants that may affect presentation of the disease and treatment outcomes. Phenotypic information will include pathology, surgical, and other clinical outcomes related to Hirschsprung disease. This study will hopefully lead to a better understanding of the genetics of HSCR and, further down the road, improved diagnosis, treatment, and genetic counseling.
This study asks volunteers to:
- Complete a medical/family history questionnaire
- Provide access to some medical records
- Submit blood samples from the individual(s) affected with Hirschsprung disease and his/her parents (if available)
Study Type
Enrollment (Estimated)
Contacts and Locations
Study Contact
- Name: Jenna Pucel, MS
- Phone Number: 212-263-8069
- Email: jenna.pucel@nyulangone.org
Study Locations
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New York
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New York, New York, United States, 10016
- Recruiting
- New York University School of Medicine
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Contact:
- Monica Erazo, MS
- Phone Number: 212-263-8069
- Email: Monica.Erazo@nyulangone.org
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Principal Investigator:
- Aravinda Chakravarti, PhD
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Sampling Method
Study Population
Description
Inclusion Criteria:
- Individuals with Hirschsprung disease and their first degree relatives (any segment length of disease, with or without other congenital anomalies or health problems, single or multiple affected individuals in family)
Exclusion Criteria:
- Unable or unwilling to provide sample for genetic studies
- Individual, parent, or guardian unable to comprehend and provide informed consent
Study Plan
How is the study designed?
Design Details
- Observational Models: Family-Based
- Time Perspectives: Prospective
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
---|---|
Families with Hirschsprung Disease
Individuals with Hirschsprung disease and their affected and unaffected relatives.
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Blood, saliva, or DNA samples are requested from all study participants.
The blood or saliva samples are used to isolate DNA in all participants.
Blood samples are also used to establish cell lines in some participants.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Discovery and characterization of common genetic variation associated with Hirschsprung disease
Time Frame: DNA is isolated up to 1 year after enrollment
|
Genome-wide assays of common genetic variation will be assessed using single nucleotide polymorphism (SNP) arrays
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DNA is isolated up to 1 year after enrollment
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Discovery and characterization of copy number variants associated with Hirschsprung disease
Time Frame: DNA is isolated up to 1 year after enrollment
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Copy number variation will be detected using next generation sequencing data and high resolution microarrays that allow for detection of copy number variants across the genome
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DNA is isolated up to 1 year after enrollment
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Discovery and characterization of rare genetic variation associated with Hirschsprung disease
Time Frame: DNA is isolated up to 1 year after enrollment
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Exome sequencing will be used to detect rare variation across all genes in the genome
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DNA is isolated up to 1 year after enrollment
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Correlation of genetic variants with location of transition zone in Hirschsprung disease
Time Frame: Baseline pathology data is obtained up to 1 year after enrollment
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Pathology records and surgical records will be used to determine transition zone
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Baseline pathology data is obtained up to 1 year after enrollment
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Correlation of genetic variants with risk for enterocolitis in Hirschsprung disease
Time Frame: Baseline clinical data is obtained up to 1 year after enrollment
|
Baseline clinical data is obtained up to 1 year after enrollment
|
|
Characterization of Hirschsprung disease that co-occurs with a known chromosomal disorder
Time Frame: Baseline clinical data is obtained up to 1 year after enrollment
|
Baseline clinical data is obtained up to 1 year after enrollment
|
|
Characterization of Hirschsprung disease that co-occurs with a known single gene syndrome
Time Frame: Baseline clinical data is obtained up to 1 year after enrollment
|
Baseline clinical data is obtained up to 1 year after enrollment
|
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Characterization of Hirschsprung disease that co-occurs with other congenital anomalies without a known diagnosis
Time Frame: Baseline clinical data is obtained up to 1 year after enrollment
|
Baseline clinical data is obtained up to 1 year after enrollment
|
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Correlation of genetic variants with need for repeat pull-through surgery in Hirschsprung disease
Time Frame: Baseline clinical data is obtained up to 1 year after enrollment and follow up data is obtained up to 100 years after enrollment
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Assessment of complications that lead to eventual repeat pull-through surgery
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Baseline clinical data is obtained up to 1 year after enrollment and follow up data is obtained up to 100 years after enrollment
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Correlation of genetic variants with difficulty controlling stools after pull-through surgery
Time Frame: Baseline clinical data is obtained up to 1 year after enrollment and follow up data is obtained up to 100 years after enrollment
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Baseline clinical data is obtained up to 1 year after enrollment and follow up data is obtained up to 100 years after enrollment
|
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Correlation of genetic variants with chronic constipation after pull-through surgery
Time Frame: Baseline clinical data is obtained up to 1 year after enrollment and follow up data is obtained up to 100 years after enrollment
|
Baseline clinical data is obtained up to 1 year after enrollment and follow up data is obtained up to 100 years after enrollment
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Aravinda Chakravarti, PhD, NYU Langone Health
Publications and helpful links
General Publications
- Badner JA, Sieber WK, Garver KL, Chakravarti A. A genetic study of Hirschsprung disease. Am J Hum Genet. 1990 Mar;46(3):568-80.
- Emison ES, McCallion AS, Kashuk CS, Bush RT, Grice E, Lin S, Portnoy ME, Cutler DJ, Green ED, Chakravarti A. A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature. 2005 Apr 14;434(7035):857-63. doi: 10.1038/nature03467.
- Gabriel SB, Salomon R, Pelet A, Angrist M, Amiel J, Fornage M, Attie-Bitach T, Olson JM, Hofstra R, Buys C, Steffann J, Munnich A, Lyonnet S, Chakravarti A. Segregation at three loci explains familial and population risk in Hirschsprung disease. Nat Genet. 2002 May;31(1):89-93. doi: 10.1038/ng868. Epub 2002 Apr 15.
- Arnold S, Pelet A, Amiel J, Borrego S, Hofstra R, Tam P, Ceccherini I, Lyonnet S, Sherman S, Chakravarti A. Interaction between a chromosome 10 RET enhancer and chromosome 21 in the Down syndrome-Hirschsprung disease association. Hum Mutat. 2009 May;30(5):771-5. doi: 10.1002/humu.20944.
- Emison ES, Garcia-Barcelo M, Grice EA, Lantieri F, Amiel J, Burzynski G, Fernandez RM, Hao L, Kashuk C, West K, Miao X, Tam PK, Griseri P, Ceccherini I, Pelet A, Jannot AS, de Pontual L, Henrion-Caude A, Lyonnet S, Verheij JB, Hofstra RM, Antinolo G, Borrego S, McCallion AS, Chakravarti A. Differential contributions of rare and common, coding and noncoding Ret mutations to multifactorial Hirschsprung disease liability. Am J Hum Genet. 2010 Jul 9;87(1):60-74. doi: 10.1016/j.ajhg.2010.06.007.
- Kapoor A, Jiang Q, Chatterjee S, Chakraborty P, Sosa MX, Berrios C, Chakravarti A. Population variation in total genetic risk of Hirschsprung disease from common RET, SEMA3 and NRG1 susceptibility polymorphisms. Hum Mol Genet. 2015 May 15;24(10):2997-3003. doi: 10.1093/hmg/ddv051. Epub 2015 Feb 9.
- Chatterjee S, Kapoor A, Akiyama JA, Auer DR, Lee D, Gabriel S, Berrios C, Pennacchio LA, Chakravarti A. Enhancer Variants Synergistically Drive Dysfunction of a Gene Regulatory Network In Hirschsprung Disease. Cell. 2016 Oct 6;167(2):355-368.e10. doi: 10.1016/j.cell.2016.09.005. Epub 2016 Sep 29.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 17-01813
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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