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While many NSHL cases associated with GSDME involve the skipping of exon 8, there is another, less understood pathogenic insertion variant specifically found in Chinese pedigrees that causes deafness, known as autosomal dominant 5 (DFNA5) hearing loss. In this study, we recruited a large Chinese pedigree, conducted whole\u2010exome and Sanger sequencing to serve as a comprehensive clinical examination, and extracted genomic DNA samples for co\u2010segregation analysis of the members. Conservation and expression analyses for GSDME were also conducted. Our clinical examinations revealed an autosomal dominant phenotype of hearing loss in the family. Genetic analysis identified a novel insertion variant in <jats:italic>GSDME<\/jats:italic> exon 8 (GSDME: NM_004403.3: c.1113_1114insGGGGTGCAGCTTACAGGGTGGGTGT: p. P372fs*36). This variant is segregated with the deafness phenotype of this pedigree. The <jats:italic>GSDME<\/jats:italic> gene was highly conserved in the different species we analysed, and its mRNA expression was ubiquitously low in different human tissues. In conclusion, we have successfully identified a novel pathogenic insertion variant of <jats:italic>GSDME<\/jats:italic> in a Chinese pedigree that causes deafness, shedding light on the genetic basis of hearing loss within this specific family. Our findings expand the spectrum of known variants associated with GSDME\u2010related deafness and may further support both the underlying gain\u2010of\u2010function mechanism and functional associations of GSDME hearing loss variants.<\/jats:p>","DOI":"10.1111\/jcmm.18004","type":"journal-article","created":{"date-parts":[[2023,10,21]],"date-time":"2023-10-21T00:49:38Z","timestamp":1697849378000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Novel, pathogenic insertion variant of <scp>GSDME<\/scp> associates with autosomal dominant hearing loss in a large Chinese pedigree"],"prefix":"10.1111","volume":"28","author":[{"given":"Jingliang","family":"Cheng","sequence":"first","affiliation":[{"name":"Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine Southwest Medical University  Luzhou 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