Molecular basis for phenotypic similarity of genetic disorders

Abstract

The contribution of distinct genes to overlapping phenotypes suggests that such genes share ancestral origins, membership of disease pathways, or molecular functions. A recent study by Liu and colleagues identified mutations in TCF20, a paralog of RAI1, among individuals manifesting a novel syndrome that has phenotypes similar to those of Smith-Magenis syndrome (a disorder caused by disruption of RAI1). This study highlights how structural similarity among genes contributes to shared phenotypes, and shows how this relationship can contribute to our understanding of the genetic basis of complex disorders.

Fig. 1

A domain-centric view of disease. The figure shows a model for how genes that share a combination of domains are more likely to show a similar set of phenotypes. In this model, genes that code for proteins 1 to N share various protein domains, including domains X, Y, and Z, and their disruption leads to phenotypes P1–P8. Frequency is defined as the number of genes that are associated with a phenotype out of all the genes that share the domain or combination of domains. Specificity for the manifestation of certain phenotypes increases as the number of shared domains increases. In this case P2–P5 show increased frequency as the number of shared domains increases while the other phenotypes are no longer associated with the increasingly complex domain combination