Oppo, Manuela (2017) Discovering rare-disease-causing genes in the Whole Exome Sequencing (WES) era: analysis of a heterogeneous cohort of families with rare Mendelian diseases. Doctoral Thesis.
Rare Mendelian diseases are estimated to be ~7,000 and while each is individually rare, together contribute significantly to morbidity, mortality, and healthcare costs. Providing a timely and molecularly defined diagnosis is the goal of the scientific community to make and adequate disease management, to find knowledge-based targeted treatments, to arrange a surveillance program for later-onset comorbidities, to provide a genetic counseling with respect to recurrence risks and prenatal diagnosis options for families. The recent development of methods for exome sequence capture, called Whole Exome Sequencing (WES) made it possible to investigate all the coding variants present in an individual human genome, allowing both the screening of unknown and known disease-genes, rapidly and cost-effectively. Taking advantage of WES, we studied a cohort of 25 families with different rare diseases like: Crisponi syndrome/Cold-induced sweating syndrome type 1, Syndromic Intellectual Disabilities, Progeroid-like syndrome, Osteopetrosis autosomic recessive, Genetic hearing loss and Epileptic Encephalopathy. We found one or more pathogenic variants in 15/25 families and putative pathogenic variant in 3/25 families. We discuss about the issues related to the study of rare diseases and to the analysis of WES data, and conclude with the statement that WES is a powerful, cost effective and rapid way to discover new genes implies in rare disease.
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