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A genetic study of Hirschsprung disease
J A Badner1, W K Sieber, K L Garver
1Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA.
American Journal of Human Genetics
|March 1, 1990
Summary
Hirschsprung disease (congenital aganglionic megacolon) inheritance varies by extent. Extensive cases suggest dominant inheritance, while limited cases may be multifactorial or recessive.
Area of Science:
- Genetics
- Pediatric Surgery
- Developmental Biology
Background:
- Hirschsprung disease (congenital aganglionic megacolon) is often considered a sex-modified multifactorial trait.
- Understanding its genetic basis is crucial for accurate recurrence risk assessment and genetic counseling.
- Previous studies suggest complex inheritance patterns, but definitive modes remain debated.
Purpose of the Study:
- To investigate the inheritance patterns of Hirschsprung disease using complex segregation analysis.
- To determine if the mode of inheritance differs based on the extent of aganglionosis.
- To evaluate the association with Down syndrome and maternal age.
Main Methods:
- Complex segregation analysis was performed on a dataset of 487 Hirschsprung disease probands and their families.
- Families were categorized based on the extent of colonic aganglionosis (limited vs. extensive).
- Demographic data, recurrence risks, and the frequency of Down syndrome were analyzed.
Main Results:
- An increased male-to-female ratio (3.9:1) and elevated sibling recurrence risk (4%) were observed compared to population incidence (0.02%).
- Sex ratio decreased and sibling recurrence risk increased with more extensive aganglionosis.
- Down syndrome occurred more frequently in affected individuals, independent of maternal age.
Conclusions:
- For Hirschsprung disease with aganglionosis extending beyond the sigmoid colon, inheritance is compatible with a dominant gene with incomplete penetrance.
- For cases limited to the sigmoid colon, inheritance is equally likely to be multifactorial or due to a recessive gene with low penetrance.
- A model involving random effects during morphogenesis aligns with observed inheritance patterns.
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