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Background: Nonsyndromic hearing loss (NSHL) is the most common sensorineural disorder and one of the most common human defects. Autosomal recessive inheritance accounts for a huge percentage of familial cases. Next‐generation sequencing (NGS) is a powerful molecular diagnostic strategy for NSHL. The combination of a microarray gene chip and NGS can better delineate the etiology and genetic cause of deafness in many cases. Methods: One hundred and thirty‐one unrelated students with NSHL who attend a special education school in Yunnan Province were recruited. Firstly, four common deafness‐related genes (GJB2, GJB3, SLC26A4, and mtDNA 12S rRNA) were evaluated for mutations using a microarray kit. Furthermore, 227 known human deafness genes were sequenced to identify the responsible genetic variant of the proband in three Chinese families with autosomal recessive hearing loss. The mutational status of family members of the probands was validated by Sanger sequencing. Results: Five novel variants were found in three families using NGS. In family 1, we identified compound heterozygosity at the MYO15A (OMIM, #600316), including an duplication variant c.3866dupC, p.His1290Alafs*25 and a 3‐bp deletion (c.10251_10253del, p.Phe3420del), resulting in protein length changes and premature protein truncation, respectively. In family 2, two affected siblings from a consanguineous Chinese Dai family harbored an c.1274G>C, p.Arg425Pro missense variant in the OTOF (OMIM, #601071). In family 3, we identified compound heterozygosity for c.129_130del, p.His43Glnfs*28 and c.76_79del, p.Lys26* in the RDX gene (OMIM, #611022). Conclusion: Five novel variants were found in three families with NSHL. Our findings extend the mutational spectrum in deafness‐related genes and will help physicians in better understanding the etiology of hearing loss. [ABSTRACT FROM AUTHOR]