Dissecting genetics of highly heterogeneous mendelian disorders: the example of Primary Ciliary Dyskinesia

Mendelian diseases characterized by high genic heterogeneity, monogenic affections caused by mutations that could occurred in a large number of genes, are delicate to investigate at both research and diagnostic levels. Recessive transmission renders the investigations even more difficult in research practice. Primary Ciliary Dyskinesia (PCD), a relatively rare congenital hereditary disorder affecting about 1/20'000 individuals, is a striking example of such condition with extensive heterogeneous genetics. The biological anomalies of PCD can be summarized by absent or reduced motility of all the ciliated and flagellated structures. Cilia and flagella are evolutionarily conserved cellular extensions playing a key role in the development and physiology of organisms. They are also critical in an increasing number of other human pathologies including developmental, renal, vision, auditory, respiratory and reproductive systems. In PCD the ciliary defect results mainly in recurrent infections of the upper respiratory airways causing sinusitis and bronchitis due to reduced mucociliary clearance. Often, the disease develops to bronchiectasis, which in extreme events requires an ablative surgery of part of lungs and/or lung transplant. In addition half of cases showing also a situs inversus are referred to as Kartagener syndrome (KS). Medical care of PCD involves only treatment of symptomatic aspects of the disease sofar. A limited fraction of the genetics causes estimated to 17-38 %, with "only" 12 known genes, have been elucidated to date, despite enormous efforts were made by analysis of familial allele segregation and sequencing of candidate genes. The recent development of methods allowing high-throughput analysis of sequence of large parts of genome even whole exome (next-generation sequencing) will likely bring a tremendous help in resolving most if not all disease causing genes in PCD and other such conditions