Dottorato in BIOLOGIA UMANA E GENETICA MEDICA

Titolo della tesi: Exome analysis of patients affected by rare disorders

Introduction: The majority of rare diseases have an underlying genetic cause for their condition and making a molecular diagnosis with current technologies and knowledge is often still a challenge. So, in this study we made retrospective analysis in which we describe the variable spectrum of molecular findings, diagnostic yield, and potential clinical impact of exome sequencing (ES) in a heterogeneous cohort of patients with genetic disorders to investigate the clinical usefulness of this approach in diagnosis and estimate its impact on the outcome of patients with rare diseases. Methods: We recruited 56 subjects affected by genetic disorders at U.O.C. Medical Genetics Laboratory (San Camillo - Forlanini Hospital, Rome), Sapienza University of Rome (Italy) which were first analyzed by ES and subsequently, by Sanger sequencing, the resulting variants were validated. ES analysis was based on dividing pathologies into 15 categories, according to the anatomical district affected by the disease in order to determine also how the diagnostic yield can differentiate within these. Results: Patients with non‐specific and complex nervous system diseases were the most prevalent indication. Primary findings (only pathogenic and likely pathogenic variants) were reported in 19/56 patients, with an overall diagnostic yield of 36%. In this cohort, the category with the greatest diagnostic power was that of blood diseases (43%). Conclusion: Our findings show evidence of a clinical benefit of ES as a diagnostic tool for patients with nonspecific or unusual disease presentations of possible genetic cause and for patients with clinical diagnoses of heterogeneous genetic conditions.