Hirschsprung Disease Genetic Study

Study Overview
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Brief Summary
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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
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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)

Official Title
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Genetic Analysis of Hirschsprung Disease

Conditions
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Hirschsprung Disease

Intervention / Treatment
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* Other: Identification of genetic causes of Hirschsprung Disease


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Week
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Families with Hirschsprung Disease<br>Individuals with Hirschsprung disease and their affected and unaffected relatives. | Other: Identification of genetic causes of Hirschsprung Disease<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Correlation of genetic variants with risk for enterocolitis in Hirschsprung disease |  | Baseline clinical data is obtained up to 1 year after enrollment | 
| Characterization of Hirschsprung disease that co-occurs with a known chromosomal disorder |  | Baseline clinical data is obtained up to 1 year after enrollment | 
| Characterization of Hirschsprung disease that co-occurs with a known single gene syndrome |  | Baseline clinical data is obtained up to 1 year after enrollment | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hirschsprung