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

• Published in: Journal of translational medicine Vol. 17; no. 1; pp. 269 - 6
• Main Authors: Ołdak, Monika, Lechowicz, Urszula, Pollak, Agnieszka, Oziębło, Dominika, Skarżyński, Henryk
• Format: Journal Article
• Language: English
• Published: London BioMed Central 14.08.2019; BioMed Central Ltd; BMC
• Subjects: Biomedical and Life Sciences; Biomedicine; Digenic inheritance; Evaluation; Genes; Genetic aspects; Genetic testing; Genetic variation; GJB2; Health aspects; Health counseling; Hearing loss; High throughput sequencing; High-throughput screening (Biochemical assaying); Medical genetics; Medicine/Public Health; Neuroscience; Risk factors; TMPRSS3; Poland; Digenic inheritance; High throughput sequencing; Hearing loss; GJB2; TMPRSS3
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-019-2018-9

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.