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Genetic Testing in Hirschsprung Disease
Genetic Testing in Hirschsprung Disease

Contributed by Sarah K Harm, MD and Jeffrey A Kant, MD, PhD


The patient is a nine month old Caucasian boy who, as a newborn, failed to pass meconium prior to his 48 hour discharge from the hospital. He was the product of an uncomplicated, term pregnancy. He went on to develop chronic constipation and was clinically diagnosed with Hirschsprung disease. Biopsies were performed and the clinical diagnosis of Hirschsprung disease was pathologically confirmed by intestinal aganlionosis involving only the rectosigmoid colon (i.e. short-segment disease). The patient had no other congenital anomalies and there was no family history of Hirschsprung disease so he was therefore classified as a case of isolated Hirschsprung disease.

What genetic testing, if any, would you perform first to support the diagnosis of Hirschsprung disease?


RET gene testing (exons 2, 3, 5, 6, 9, 10, 12, 13 & 17)


Inactivating mutations of the RET gene, located on chromosome 10q11.2, are associated with Hirschsprung disease. The RET gene encodes a receptor tyrosine kinase expressed primarily in neural crest and urogenital precursor cells. [1] Disease-associated mutations have been identified scattered throughout the gene; however, most commonly are found in exons 2, 3, 5, 6, 9, 10, 12, 13 & 17. [2,3] Most mutations are missense or nonsense codon changes. A few splice-site mutations have been reported as well as large and small deletions.

Additional genes associated with isolated Hirschsprung disease have been identified but occur with frequencies much less than that of the RET gene [Table 1]. Although RET is the primary gene underlying Hirschsprung disease, particularly in long-segment disease, RET mutations show incomplete, sex-dependent penetrance and do not always result in the Hirschsprung phenotype. [2,3] Importantly, a negative RET mutation analysis does not rule out an underlying genetic etiology.

Table 1: Genes associated with isolated Hirschsprung disease. Adapted from GeneReviews. [4]

To see the entire case details from the University of Pittsburgh, CLICK HERE

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