Over the past two decades, the field of Genetics has witnessed a fantastic revolution driven by continuous technological breakthroughs. Since the completion of the human genome project, these technologies have allowed us to “read” any human genome in a short time and at reasonable cost. Nevertheless, we are still facing major challenges in the interpretation of the acquired sequences. As a result, predicting phenotype (the clinical features) based on genotype (the genetic changes) remains a major challenge.
This is particularly well illustrated in a group of human disorders called ciliopathies, which are caused by dysfunction of a cellular organelle – the primary cilium – required for sensing signals from the cellular environment. Cilia are present on most cells of our bodies and their dysfunction can therefore cause symptoms in most organs. Typical clinical features seen in ciliopathies are central nervous system malformations or dysfunction, leading to intellectual disability and neurological symptoms, retinal degeneration, fibro-cystic renal or hepatic disease, endocrinological disturbances and skeletal problems. Over 35 ciliopathies have been described, with ~200 associated genes, where dysfunction of most of these genes can cause a wide range of distinct clinical features within the ciliopathy spectrum. Given this prominent variability, we cannot predict to date which of the ciliopathy-associated clinical features will occur in a given individual based on their genetic change. This substantially complicates medical management, for example in a prenatal setting or to determine who requires surveillance measures and early intervention for progressive features such as retinal degeneration or kidney disease.