Genetic sequencing alone doesn't offer a true picture of human disease, say researchers at Duke University Medical Center.
They have shown that functional tests are absolutely necessary to understand the biological relevance of the results of sequencing studies as they relate to disease, using a suite of diseases known as the ciliopathies, which can cause patients to have many different traits.
"We have to know the extent to which gene variants in question are detrimental - how do they affect individual cells or organs and what is the result on human development or disease?" said lead author Erica Davis.
"Every patient has his or her own set of genetic variants, and most of these will not be found at sufficient frequency in the general population so that anyone could make a clear medical statement about their case," he said.
Working in collaboration with many ciliopathy labs worldwide, Davis sequenced a gene, TTC21B, known to be a critical component of the primary cilium, an antenna-like projection critical to cell function.
While a few of the mutations could readily be shown to cause two main human disorders, a kidney disease and an asphyxiating thoracic condition, the significance of the majority of DNA variants could not be determined.
Davis then tested these variants in a zebrafish model, in which many genes are similar to humans, and showed that TTC21B appears to contribute disease-related mutations to about 5 percent of human ciliopathy cases.
In ciliopathies such as Bardet-Biedl Syndrome, the primary cilium of cells is abnormal and leads to a host of problems.
The study shows how genetic variations both can cause ciliopathies and also interact with other disease-causing genes to yield very different sets of patient problems.
The study appeared in Nature Genetics online on Jan. 23.