G.P.266: Large copy number variations in NEB are frequent in nemaline myopathy patients

Abstract

Recently, new large mutations have been identified in the nebulin gene (<i>NEB</i>) causing nemaline myopathy (NM). NM constitutes a heterogeneous group of disorders among the congenital myopathies, and mutations in <i>NEB</i> are a main cause of the recessively inherited form. <i>NEB</i> consists of 183 exons and it includes a 32kb triplicate region (TRI) where eight exons are repeated three times. We have designed a custom NM-CGH microarray to detect copy number variations in the currently known nine NM genes and one unpublished gene. To date, 250 samples from 185 NM families have been run with the NM-CGH microarray and we have identified <i>NEB</i> TRI variation in approximately 16% of the NM families in this study cohort. This variation seems to be equally common in the control population, but more samples need to be studied. The results suggest that the adjacent intronic repeat elements may predispose to the recurrent TRI variations. However, the copy number of these variants differs in different samples. The possible pathogenicity of some of the TRI variations warrants further studies and elucidation of the exact breakpoints in each family. Moreover, we have identified nine different, novel, large disease-causing aberrations in <i>NEB</i> in nine different families. The size of the aberrations varies greatly, covering from only a part of one exon (0.9kb) to more than half of the gene (133kb). The NM-CGH microarray method is currently available for mutation analysis in our laboratory. Additionally we have analyzed ten samples with exome sequencing and identified causative mutations for half of the families. We believe that the combination of the NM-CGH microarray followed by exome sequencing will accelerate mutation detection and improve the diagnostics of NM and related disorders.