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Solving the genetics of a complex disorder


An international team of researchers has dissected the complex genetics of Hirschsprung disease, an inherited intestinal disorder. The new study suggests that it is possible to determine the specific contributions of individual genes in complex disorders, something that has until now proved extremely difficult to do.

Chromosome 9 and 10 from multipoint nonparametric genome scan of S-HSCR. View full

The researchers used large amounts of clinical data on Hirschsprung disease and genome scans to identify parts of three chromosomes associated with the disorder. They found that a gene on chromosome 10, called RET, and two as-yet unidentified genes act jointly to cause the 'short-segment' form of Hirschsprung disease.

The research team analyzed the DNA of 49 families with the 'short-segment' form of Hirschsprung disease. Each family had two or more affected members. Aravinda Chakravarti, of Case Western Reserve University School of Medicine in Cleveland, led the research. Chakravarti is now director of the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins University in Baltimore.

RET appears to be the main susceptibility gene for the disease. The other two genes on chromosomes 3 and 19 may, in some cases, modify the expression of RET. The researchers found that some subjects had normal RET genes, but they had mutations nearby in DNA that regulates the activity of RET.

The action of RET and the two other genes "seem to be necessary and sufficient" to cause the 'short-segment' form of the disease, although other models of the disease cannot be ruled out, the researchers conclude in Nature Genetics.

The study represents "the first complete genetic dissection" of a multifactorial disorder, according to Eberhard Passarge, of the Institut für Humangenetik, Universitätsklinikum Essen in Germany, who wrote a News and Views article accompanying the findings in Nature Genetics.

"Their approach should serve as a model for the analysis of other complex diseases with nonmendelian inheritance patterns," Passarge writes. A prerequisite for any such study is reliable clinical data characterizing the disease, he adds.

Hirschsprung disease occurs four times more often in males than in females, and the mutations associated with the disorder are not transmitted from parent to child according to any known inheritance pattern. Siblings of affected individuals are at much greater risk for the disease than others in the general population.

The new model of the disease is consistent with the recurrence risk found in siblings, the incidence of the disease in the population and what is known about the transmission of disease-related mutations between generations, according to Passarge.

Hirschsprung disease occurs in about one in 5,000 newborns. The symptoms and severity of the disease vary; the primary cause is an absence of nerve cells in the colon that prevent it from relaxing. This can lead to chronic constipation and an extended abdomen. Doctors treat the disease by surgically removing the affected portion of the colon.

The Danish pediatrician Harald Hirschsprung first described the disease in the nineteenth century, although the lack of intestinal ganglion cells was not recognized as the cause until 1948.

In 1888, Hirschsprung wrote, "[My first specimen] is a colon, but a colon of such a size that it will no doubt surprise you to learn that it comes from a child only 11 months old when it died…. Only [the] rectum was not dilated, nor indeed subject to any obstruction."

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Gabriel, S.B. et al. Segregation at three loci explains familial and population risk in Hirschsprung disease. Nat Genet. Published online April 15, 2002.
Passarge, E. Dissecting Hirschsprung disease. Nat Genet. Published online April 15, 2002.
Hirschsprung, H. Stuhletragheit Neugeborener in folge von Dilatation und Hypertrophie des Colons. Jahrb Kinderheilk 27, 1-7 (1888). [As cited in Roed-Peterson, K. & Erichsen, G. The Danish pediatrician Harald Hirschsprung. Surg Gynecol Obstet 166, 181-185 (February 1988)].

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