Badner J A, Sieber W K, Garver K L, Chakravarti A
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA.
Am J Hum Genet. 1990 Mar;46(3):568-80.
Hirschsprung disease, or congenital aganglionic megacolon, is commonly assumed to be a sex-modified multifactorial trait. To test this hypothesis, complex segregation analysis was performed on data on 487 probands and their families. Demographic information on probands and the recurrence risk to relatives of probands are presented. An increased sex ratio (3.9 male:female) and an elevated risk to sibs (4%), as compared with the population incidence (0.02%), are observed, with the sex ratio decreasing and the recurrence risk to sibs increasing as the aganglionosis becomes more extensive. Down syndrome was found at an increased frequency among affected individuals but not among their unaffected sibs, and the increase was not associated with maternal age. Complex segregation analysis was performed on these family data. The families were classified into separate categories by extent of aganglionosis. For cases with aganglionosis beyond the sigmoid colon, the mode of inheritance is compatible with a dominant gene with incomplete penetrance, while for cases with aganglionosis extending no farther than the sigmoid colon, the inheritance pattern is equally likely to be either multifactorial or due to a recessive gene with very low penetrance. A model of gene action with random effects during morphogenesis is compatible with our observations.
先天性巨结肠症，即先天性无神经节性巨结肠，通常被认为是一种受性别影响的多因素性状。为验证这一假设，对487名先证者及其家族的数据进行了复杂分离分析。文中呈现了先证者的人口统计学信息以及先证者亲属的复发风险。与人群发病率（0.02%）相比，观察到性别比增加（男性:女性为3.9:1），同胞复发风险升高（4%），随着无神经节症范围扩大，性别比降低，同胞复发风险增加。在患病个体中发现唐氏综合征的频率增加，但在其未患病的同胞中未增加，且这种增加与母亲年龄无关。对这些家族数据进行了复杂分离分析。根据无神经节症的范围将家族分为不同类别。对于无神经节症超过乙状结肠的病例，遗传模式与具有不完全外显率的显性基因相符，而对于无神经节症不超过乙状结肠的病例，遗传模式同样可能是多因素的，或者是由于具有极低外显率的隐性基因。形态发生过程中具有随机效应的基因作用模型与我们的观察结果相符。
