NEXT GENERATION SEQUENCING AND EXPERIMENTAL MYOLOGY: P.378Clinical nonsense mutations in neuromuscular disorders

Abstract

Nonsense mutations (NM) are single base substitutions that introduce a premature stop codon. There are 5218 single gene disorders and traits (OMIM), and neuromuscular disorders (NMD) represent ̴ 9% of all known Mendelian phenotypes. We present the most frequent NM that produce an NMD, in the clinical realm; as an initial step to analyze the potential benefit of emerging nonsense readthrough therapies. Accessing the free-open-database of ClinVar, a tool to facilitate the evaluation of variation-phenotype relationships, we were able to download data submitted by 17 different laboratories offering diagnostic testing for clinical purposes, across NA and Europe, which were trusted and major contributors to ClinVar. We collected only ``Clinical'' and ``nonsense mutations'' obtaining 10426 different mutations of 1094 genes, of which 1022 were likely pathogenic/pathogenic and 7821 pathogenic. Excluding oncogenes, there are 5736 NM in 1044 different monogenic disease (MD) genes. One thousand and fifty-five different variations of 96 genes were related to a NMD phenotype representing the 18.4% of all NM that can cause a MD. The most frequent NMD with an NM were TTN related phenotypes (256 mutations, representing 4.4% of all NM), and DMD (234 mutations, representing 4% of all NM). Other frequent NM and NMD phenotype were: DYSF, MTM1, and LMNA. We also classify the disease severity ranging from lethal to chronic progressive. The data obtained in this analysis represents real-world clinical information which we can use to understand the potential impact of an efficient nonsense mutation read-through agent.