Author(s): Neri M.; Scotton C.; Selvatici R.; Gualandi F.; Ferlini A.; Wirth B.; Schols L.; Klockgether T.; Lochmuller H.; Muntoni F.; D’Amico A.; Bertini E.; Pane M.; Mercuri E.

Source: Acta Myologica; 2017; vol. 36 (no. 2); p. 99

Publication Date: 2017

Publication Type(s): Conference Abstract

Abstract:The heterogeneous genetic landscape of NMDs raises challenges regarding the definition of a molecular diagnosis, now becoming mandatory for the inclusion in emerging therapeutic trials. To improve the diagnostic definition in our NMDs patients we used a Next Generation Sequencing approach: clinical gene panel analysis for the screening of known genes, WES (whole exome sequencing) and WGS (whole genome sequencing) analysis aimed at the identification of novel causative genes. WES analysis was performed in 6 “families of four” and 2 “trios”: 3 of them with congenital myopathy/dystrophy, 1 with spastic paraplegia, 2 with ataxia, 1 with Myofibrillar Myopathy, and 1 with AV block and LGMD. WES analysis unraveled the genetic cause of 5 out of 8 families. We identified 3 mutations in known genes (RYR1, ISPD and STIM1) and 2 novel causative genes POPDC1 and MSTO1, functionally validated. In the remaining 3 families, 2 candidate genes SARS2 and MMP8 were identified however not similar phenotypes were observed within the project making difficult the variation clinical validation. The WES in the last family identified a compound heterozygosis in the CPSF3L gene and transcript analysis is ongoing. Moreover, we performed WES analysis in 2 families with Bethlem myopathy and in 2 patients affected by Ullrich muscular dystrophy with no identified mutation in COL6 genes. The WES output data were prioritized on the basis of a list of 115 candidate genes involved in CollagenVI myopathy (clinical exome). All the prioritized variants were validated by Sanger and functional validation by pathway analysis is ongoing.

Database: EMBASE