How to Approach Direct-to-Consumer Genetic Testing With Your Patients.

Direct-to-consumer genetic testing (DTC-GT) is genetic testing initiated by a consumer through a commercial company without the direct involvement of a physician or genetics professional. DTC-GT companies have developed tests that provide information about one's ancestry, carrier status, and risk to develop certain conditions. As more consumers participate in DTC-GT, primary care providers (PCPs) are at a greater chance to encounter DTC-GT results and conversations in their practice. PCPs often do not have specialized genetics training and may not feel equipped to engage in a discussion about DTC-GT, but they are well-positioned to explore the perceived benefits and limitations of DTC-GT with their patients. Limitations of DTC-GT include risk for false positive or false negative results, risk for unintended information, and risk for privacy invasion. We provide a resource for PCPs to use when approaching the topic of DTC-GT with their patients including how to discuss motivations for pursuing and concerns about DTC-GT, as well as the limitations and implications of this testing. We hope this resource can guide fruitful conversations between PCPs and patients who are looking for support from their trusted physician while considering DTC-GT or interpreting their results.

Novel loss-of-function mutations in COCH cause autosomal recessive nonsyndromic hearing loss.

COCH is the most abundantly expressed gene in the cochlea. Unsurprisingly, mutations in COCH underly hearing loss in mice and humans. Two forms of hearing loss are linked to mutations in COCH, the well-established autosomal dominant nonsyndromic hearing loss, with or without vestibular dysfunction (DFNA9) via a gain-of-function/dominant-negative mechanism, and more recently autosomal recessive nonsyndromic hearing loss (DFNB110) via nonsense variants. Using a combination of targeted gene panels, exome sequencing, and functional studies, we identified four novel pathogenic variants (two nonsense variants, one missense, and one inframe deletion) in COCH as the cause of autosomal recessive hearing loss in a multi-ethnic cohort. To investigate whether the non-truncating variants exert their effect via a loss-of-function mechanism, we used minigene splicing assays. Our data showed both the missense and inframe deletion variants altered RNA splicing by creating an exon splicing silencer and abolishing an exon splicing enhancer, respectively. Both variants create frameshifts and are predicted to result in a null allele. This study confirms the involvement of loss-of-function mutations in COCH in autosomal recessive nonsyndromic hearing loss, expands the mutational landscape of DFNB110 to include coding variants that alter RNA splicing, and highlights the need to investigate the effect of coding variants on RNA splicing.