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<i>GSDME</i>, also known as <i>DFNA5</i>, is a gene implicated in autosomal dominant nonsyndromic hearing loss (ADNSHL), affecting, at first, the high frequencies with a subsequent progression over all frequencies. To date, all the <i>GSDME</i> pathogenic variants associated with deafness lead to skipping of exon 8. In two families with apparent ADNSHL, massively parallel sequencing (MPS) integrating a coverage-based method for detection of copy number variations (CNVs) was applied, and it identified the first two causal <i>GSDME</i> structural variants affecting exon 8. The deleterious impact of the c.991-60_1095del variant, which includes the acceptor splice site sequence of exon 8, was confirmed by the study of the proband’s transcripts. The second mutational event is a complex rearrangement that deletes almost all of the exon 8 sequence. This study increases the mutational spectrum of the <i>GSDME</i> gene and highlights the crucial importance of MPS data for the detection of <i>GSDME</i> exon 8 deletions, even though the identification of a causal single-exon CNV by MPS analysis is still challenging.