Hirschsprung Disease Genetic Study

• ClinicalTrials.gov Identifier: NCT00478712
• Recruitment Status: Recruiting
• First Posted: May 25, 2007
• Last Update Posted: March 9, 2021
• Sponsor: NYU Langone Health
• Collaborator: New York University
• Information provided by (Responsible Party): NYU Langone Health

Study Description

Brief 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.

Condition or disease	Intervention/treatment
Hirschsprung Disease	Other: Identification of genetic causes of Hirschsprung Disease

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:

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)

Study Design

• Study Type: Observational
• Estimated Enrollment: 3000 participants
• Observational Model: Family-Based
• Time Perspective: Prospective
• Official Title: Genetic Analysis of Hirschsprung Disease
• Actual Study Start Date: January 2001
• Estimated Primary Completion Date: August 2025
• Estimated Study Completion Date: August 2025

Groups and Cohorts

Group/Cohort	Intervention/treatment
Families with Hirschsprung Disease; Individuals with Hirschsprung disease and their affected and unaffected relatives.	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.

Outcome Measures

Primary Outcome Measures :

1. 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
2. Discovery and characterization of copy number variants associated with Hirschsprung disease [ Time Frame: DNA is isolated up to 1 year after enrollment ]
   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
3. Discovery and characterization of rare genetic variation associated with Hirschsprung disease [ Time Frame: DNA is isolated up to 1 year after enrollment ]
   Exome sequencing will be used to detect rare variation across all genes in the genome

Secondary Outcome Measures :

1. 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 ]
   Pathology records and surgical records will be used to determine transition zone
2. Correlation of genetic variants with risk for enterocolitis in Hirschsprung disease [ Time Frame: Baseline clinical data is obtained up to 1 year after enrollment ]
3. 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 ]
4. 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 ]
5. 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 ]
6. 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 ]
   Assessment of complications that lead to eventual repeat pull-through surgery
7. 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 ]
8. 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 ]

Biospecimen Retention:   Samples With DNA

Study volunteers are asked to provide blood or cheek swab/saliva samples. DNA is extracted from the samples for use in the study.

Eligibility Criteria

• Ages Eligible for Study: up to 100 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

The study population includes individuals with Hirschsprung disease and their family members.

Criteria

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

Contacts and Locations

Contacts

Contact: Monica Erazo, MS; 212-263-8069; Monica.Erazo@nyulangone.org

Locations

United States, New York

New York University School of Medicine; Recruiting

New York, New York, United States, 10016

Contact: Monica Erazo, MS 212-263-8069 Monica.Erazo@nyulangone.org

Principal Investigator: Aravinda Chakravarti, PhD

Sponsors and Collaborators

NYU Langone Health

New York University

Investigators

• Principal Investigator: Aravinda Chakravarti, PhD; NYU Langone Health

More Information

Additional Information:

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

Publications of Results:

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.

Gabriel SB, Salomon R, Pelet A, Angrist M, Amiel J, Fornage M, Attié-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. 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, Antiñolo 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.

Other 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.

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT00478712
• Other Study ID Numbers: 17-01813
• First Posted: May 25, 2007
• Last Update Posted: March 9, 2021
• Last Verified: March 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by NYU Langone Health:

Hirschsprung

Additional relevant MeSH terms:

Hirschsprung Disease; Digestive System Abnormalities; Digestive System Diseases; Megacolon; Colonic Diseases; Intestinal Diseases; Gastrointestinal Diseases; Congenital Abnormalities