Progress in Human Genetics

Highlights of the 54th Annual Meeting of the American Society of Human Genetics; October 26-30, 2004; Toronto, Ontario, Canada

Sara M. Mariani, MD, PhD

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In This Article

Hirschsprung's Disease -- RET Enhancer Mutations

Hirschsprung's disease, which affects 1 in 5000 individuals, is more frequent in men than women (ratio, 4:1) and it is inheritable in 100% of cases, following a nonmendelian pattern. It is characterized by a lack of ganglion cells in the large bowel that may lead to functional obstruction and colonic dilation proximal to the segment affected. Results presented by Emison and colleagues,[19] of the NIH Intramural Sequencing Center, on the successful mapping of this genetic defect, underscore how integration of multiple genetic techniques may lead to the identification of rare disease variants in humans.

Mutations in the RET gene with loss of function are detectable in 50% of patients, which lead to decreased signaling by the glial cell-line-derived neurotrophic factor. But what is the genetic defect in the other patients? Perhaps, mutations in the noncoding sequences of the RET gene or in RET-related genes (eg, GALNACT2 and RASGEF1A)?

Analysis of the multispecies conserved sequence (MCS) in the 350-kilobase (kb) region near RET showed an overlapping pattern of genes in this domain. A transmission disequilibrium test yielded distortion for single-nucleotide polymorphism markers associated with the RET intron 1 -- SFC1 in intron 1 was consistently transmitted to the affected progeny (79% of cases). Overlay of the association results with comparative genomics datasets revealed that MCS+9.7 acts as an enhancer in vitro, in the neuroblastoma cell line Neuro2a. Mutations in MCS+9.7 RET enhancer led to a 6.3-fold reduction in its enhancing activity.[19,20,21]

The MCS+9.7 RET enhancer mutation is transmitted more frequently by the mother, and it shows a substantial geographic variation: The mutation is absent in Africa (< 5% of cases), present in Europe (> 25%), and most frequent in Eastern Asia (eg, Japan and China, > 40%). Other factors must then modify the clinical manifestations of Hirschsprung's disease. Of note, because only .48% of 7855 single-nucleotide polymorphisms in the HapMap show a distribution similar to that of MCS+9.7, such a genetic variant of the RET enhancer may have provided a selective advantage in the heterozygous state, linked to its uneven geographical distribution.[19]

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