Hirschsprung Disease Genetic Study

Hirschsprung Disease Clinical Trial

Official title:

Genetic Analysis of Hirschsprung Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00478712
• Other study ID #: 17-01813
• Status: Recruiting
• Start date: January 2001
• Est. completion date: December 2028

Study information

• Verified date: November 2023
• Source: NYU Langone Health
• Contact: Jenna Pucel, MS
• Phone: 212-263-8069
• Email: jenna.pucel[@]nyulangone.org
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Hirschsprung disease is a genetic condition caused by lack of nerve cells in varying lengths of the intestines. This study will investigate the complex genetic basis of the disease, which involves multiple interacting genetic factors.

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: 1. Complete a medical/family history questionnaire 2. Provide access to some medical records 3. Submit blood samples from the individual(s) affected with Hirschsprung disease and his/her parents (if available)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 3000
• Est. completion date: December 2028
• Est. primary completion date: December 2028
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 1 Week to 100 Years

Eligibility

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

Related Conditions & MeSH terms

• Hirschsprung Disease

Intervention

Other:
• Identification of genetic causes of Hirschsprung Disease
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.

Locations

Country	Name	City	State
United States	New York University School of Medicine	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
NYU Langone Health	New York University

Country where clinical trial is conducted

United States, 

References & Publications (7)

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) — View Citation

Badner JA, Sieber WK, Garver KL, Chakravarti A. A genetic study of Hirschsprung disease. Am J Hum Genet. 1990 Mar;46(3):568-80. — View Citation

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. — View Citation

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, Borr — View Citation

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/nature03 — View Citation

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 — View Citation

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Discovery and characterization of common genetic variation associated with Hirschsprung disease	Genome-wide assays of common genetic variation will be assessed using single nucleotide polymorphism (SNP) arrays	DNA is isolated up to 1 year after enrollment
Primary	Discovery and characterization of copy number variants associated with Hirschsprung disease	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	DNA is isolated up to 1 year after enrollment
Primary	Discovery and characterization of rare genetic variation associated with Hirschsprung disease	Exome sequencing will be used to detect rare variation across all genes in the genome	DNA is isolated up to 1 year after enrollment
Secondary	Correlation of genetic variants with location of transition zone in Hirschsprung disease	Pathology records and surgical records will be used to determine transition zone	Baseline pathology data is obtained up to 1 year after enrollment
Secondary	Correlation of genetic variants with risk for enterocolitis in Hirschsprung disease		Baseline clinical data is obtained up to 1 year after enrollment
Secondary	Characterization of Hirschsprung disease that co-occurs with a known chromosomal disorder		Baseline clinical data is obtained up to 1 year after enrollment
Secondary	Characterization of Hirschsprung disease that co-occurs with a known single gene syndrome		Baseline clinical data is obtained up to 1 year after enrollment
Secondary	Characterization of Hirschsprung disease that co-occurs with other congenital anomalies without a known diagnosis		Baseline clinical data is obtained up to 1 year after enrollment
Secondary	Correlation of genetic variants with need for repeat pull-through surgery in Hirschsprung disease	Assessment of complications that lead to eventual repeat pull-through surgery	Baseline clinical data is obtained up to 1 year after enrollment and follow up data is obtained up to 100 years after enrollment
Secondary	Correlation of genetic variants with difficulty controlling stools after pull-through surgery		Baseline clinical data is obtained up to 1 year after enrollment and follow up data is obtained up to 100 years after enrollment
Secondary	Correlation of genetic variants with chronic constipation after pull-through surgery		Baseline clinical data is obtained up to 1 year after enrollment and follow up data is obtained up to 100 years after enrollment

External Links

•   Chakravarti, Johns Hopkins Medical Institution (JHMI) Faculty Biography Page