Exome Sequencing in the Diagnostics of non-motile Ciliopathies (114 cases)

Background: Non-motile cilia are hair like structures extending from the surface of most cells in mammalian organisms. Mutations in genes encoding for cilia associated proteins lead to complex developmental defects and although individual ciliopathy diseases are very rare, together they represent a significant disease burden. Due to extensive genetic heterogeneity and phenotypic as well as genetic overlap, molecular diagnosis using Sanger sequencing has been proven very difficult in the past. However, the development of Next Generation Sequencing techniques such as Whole Exome Sequencing (WES) offers new diagnostic tools. Results: We have investigated 61 Jeune Asphyxiating Thoracic Dysplasia (JATD), 37 Bardet-Biedl-Syndrome (BBS), 7 Joubert and 9 other ciliopathy cases (total of 113 cases) using WES and were able to identify the disease causing gene in approximately two thirds of all cases with about 50% of JATD and Joubert cases but up to 90% of BBS cases being caused by known disease causing genes. Our findings lead to revision of the clinical diagnosis in some cases and revealed new phenotype-genotype associations, especially in JATD. Functional studies for several new genes identified are currently under investigation. However, the proportion of solved cases was much lower among less well defined phenotypes. Summary: Our findings in this large non-motile ciliopathy cohort demonstrate that WES is a very efficient tool in genetics diagnosis of heterogenous recessive disorders and shows that this is facilitated by deep phenotyping. Compared to NGS gene panel sequencing, WES offers additional opportunities to identify new genes previously not associated with the condition investigated.