Diagnostic Whole Exome Sequencing to Study a Cohort of Greek Patients with Heterogeneous Neurological and Other Disorders (P5.134)

Objective: Our aim here was to evaluate the diagnostic efficacy of Whole Exome Sequencing (WES) in a cohort of Greek patients with heterogeneous neurological and non-neurological syndromes. Background: Next generation sequencing technologies, including WES, are increasingly employed in the investigation of neurological and other diseases. However, use of WES in daily neurological practice has not been adequately studied. Design/Methods: Patients presenting to study clinicians with disorders (mainly neurological) suspected to be genetic in origin were offered WES on the basis of predefined criteria. After obtaining informed consent, WES was performed on 67 patients (24 females and 43 males; mean age=18.24±20.71yrs, range 0.8-71yrs) aiming at a 50X coverage. Data analyses and variant annotation were performed in the Neurology Laboratory, University of Crete, Greece, taking into account available clinical information and bibliographic data. Sanger sequencing was used to verify positive findings. Results: The overall diagnostic rate of WES was 43.3 [percnt] (29/67 patients). Specifically, causal variants were identified in the following genes: ALDOB (hereditary fructose intolerance), ANO5 (muscular dystrophy), ATL1 (spastic paraplegia), CAPN3 (muscular dystrophy), CJB2 (deafness), CLCN1 (congenital myotonia), COMP (pseudo-achondroplasia), CPT2 (rhabdomyolysis, 2 cases), EPM2A (Lafora disease), ETFDH (AcylCoA dehydrogenase deficiency), FIG4 (CMT4J), GAA (Pompe disease), GRIN2B (epilepsy), ISPD (muscular dystrophy), LMNA (laminopathy), NDRG1 (CMT4D), NF1 (Neurofibromatosis type I), NIPBL (Cornelia de Lange syndrome), NSD1 (Sotos syndrome), PAX6 (nystagmus/aniridia syndrome), SCN1A (epilepsy, 2 cases), SCN10A (Brugada syndrome), SLC12A1 (Bartter syndrome), SLC16A2 (Allan-Herndon-Dudley syndrome), PDHX (lactic acidosis), SYNE1 (muscular dystrophy) and TARDBP (ALS/FTLD). In most of the cases, WES provided final diagnosis after several costly and laborious diagnostic tests were inconclusive. Conclusions: In our cohort of patients with neurological and non-neurological syndromes, WES showed high diagnostic yield and was cost effective. These data offer support to the value of WES to end the diagnostic conundrum of patients with heterogeneous neurogenetic disorders.