Clinical trial NCT00478712: Hirschsprung Disease Genetic Study
Official title: Genetic Analysis of Hirschsprung Disease
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Hirschsprung Disease
Keywords: Hirschsprung
Lead sponsor: NYU Langone Health
Sponsor class: OTHER
Collaborators: name: New York University
First posted: 2007-05-25
Enrollment: 3000
Sex: ALL
Minimum age (years): 1
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: FAMILY_BASED
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population includes individuals with Hirschsprung disease and their family members.

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.

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)

Eligibility 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

Primary outcomes:
measure: Discovery and characterization of common genetic variation associated with Hirschsprung disease
timeFrame: DNA is isolated up to 1 year after enrollment
measure: Discovery and characterization of copy number variants associated with Hirschsprung disease
timeFrame: DNA is isolated up to 1 year after enrollment
measure: Discovery and characterization of rare genetic variation associated with Hirschsprung disease
timeFrame: DNA is isolated up to 1 year after enrollment
Secondary outcomes:
measure: Correlation of genetic variants with location of transition zone in Hirschsprung disease
timeFrame: Baseline pathology data is obtained up to 1 year after enrollment
measure: Correlation of genetic variants with risk for enterocolitis in Hirschsprung disease
timeFrame: Baseline clinical data is obtained up to 1 year after enrollment
measure: Characterization of Hirschsprung disease that co-occurs with a known chromosomal disorder
timeFrame: Baseline clinical data is obtained up to 1 year after enrollment
measure: Characterization of Hirschsprung disease that co-occurs with a known single gene syndrome
timeFrame: Baseline clinical data is obtained up to 1 year after enrollment
measure: Characterization of Hirschsprung disease that co-occurs with other congenital anomalies without a known diagnosis
timeFrame: Baseline clinical data is obtained up to 1 year after enrollment
measure: Correlation of genetic variants with need for repeat pull-through surgery in Hirschsprung disease
timeFrame: Baseline clinical data is obtained up to 1 year after enrollment and follow up data is obtained up to 100 years after enrollment
measure: Correlation of genetic variants with difficulty controlling stools after pull-through surgery
timeFrame: Baseline clinical data is obtained up to 1 year after enrollment and follow up data is obtained up to 100 years after enrollment
measure: Correlation of genetic variants with chronic constipation after pull-through surgery
timeFrame: Baseline clinical data is obtained up to 1 year after enrollment and follow up data is obtained up to 100 years after enrollment
Other outcomes:
Locations:
city: New York
country: United States
facility: New York University School of Medicine
state: New York
Study officials:
affiliation: NYU Langone Health
name: Aravinda Chakravarti, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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/nature03467.
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. 2002 May;31(1):89-93. doi: 10.1038/ng868. Epub 2002 Apr 15.
citation: 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.
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, 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.
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. doi: 10.1093/hmg/ddv051. Epub 2015 Feb 9.
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: 10.1016/j.cell.2016.09.005. Epub 2016 Sep 29.