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Background  Hearing loss (HL) is the most common disability of human senses characterized by a great allelic heterogeneity.  GJB2  and  TMPRSS3  are two well-known HL genes typically underlying its monogenic form. Recently,  TMPRSS3/GJB2  digenic inheritance has been proposed. As results of genetic testing can be easily overinterpreted, we aimed to verify the hypothesis.    Methods  From genetic database of HL patients with at least one  TMPRSS3  pathogenic variants we have selected individuals with additional  GJB2  pathogenic variants. All of the available family members were recruited for the study. Segregation analysis of the respective  TMPRSS3  and  GJB2  pathogenic variants was performed within the families.    Results  The strategy has allowed to identify four individuals who were double heterozygous for known pathogenic  TMPRSS3  and  GJB2  variants. Two individuals from different families had  GJB2  c.35delG and  TMPRSS3  c.208delC and in two other individuals from one family  GJB2  c.35delG together with  TMPRSS3  c.1343T>C variants were found. None of these subjects has ever reported hearing problems and their hearing status was normal.    Conclusions  Our data provide evidence against  TMPRSS3 / GJB2  digenic inheritance of HL. As high throughput sequencing is increasingly used for genetic testing, particular caution should be taken to provide the patients with accurate genetic counseling.

Overinterpretation of high throughput sequencing data in medical genetics: first evidence against TMPRSS3/GJB2 digenic inheritance of hearing loss