Genomic Variation in Multigenic Traits: Hirschsprung Disease

Abstract

Recent advances in genomic technology and the availability of a finished human genome sequence havegreatly facilitated the identification of genes underlyinghuman Mendelian disorders. The contemporary challenge lies in the elucidation of complex disorders. Classically, the transmission of a Mendelian disorder is explained by the exact co-segregation of a single mutationwith the phenotype. Such mutations are absent in controlsand, most frequently, involve conserved coding sequences. These observations are in stark contrast to thecomplex non-Mendelian diseases, wherein mutations atsingle genes do occur in unaffecteds, and variants withweak or moderate quantitative effects on the phenotypeplay a significant role. Consequently, such mutationsmay exist at relatively high frequency in the generalpopulation...