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Sequencing Study Reveals Role of RIPOR2 Mutation in Adult-Onset Hearing Loss

NEW YORK – One of the most widespread disabilities in the world is hearing loss and the adult-onset form of this condition is highly heritable, but the genetic causes are poorly understood. However, recent findings related to a genetic variant have shed some light on the matter and provide a novel candidate for hearing loss gene therapy.

Reporting in the British Medical Journal on Monday, researchers from Radboud University in Nijmegen, the Netherlands, discovered an in-frame deletion of 12 nucleotides in RIPOR2 that is responsible for adult-onset progressive hearing loss. Many thousands of people are potentially at risk for hearing loss if they inherit this common genetic variant, they wrote. 


"We started the study because members of several families with mostly adult-onset hearing loss came to the outpatient clinics with the story that many family members were affected," said Radboud University's Hannie Kremer, corresponding author on the study, in an email.  


The in-frame deletion (c.1696_1707del; NM_014722.3) in RIPOR2 (RHO family interacting cell polarization regulator 2) was classified as an autosomal dominant trait in the 12 families of Dutch origin that the team studied. RIPOR2 had previously been associated with recessively inherited early-onset hearing loss. Before they identified the variant, they had already determined the locus involved in hearing loss on chromosome 6 (p24.1–22.3): DFNA21. 


To identify the variant, they carried out exome sequencing in three affected members of a Dutch family. In total, they studied 12 families, comprising 200 people. The researchers assessed 200 affected and unaffected individuals from seven families and five single index cases between 1997 and 2018. Each individual received a general ear, nose, and throat exam along with a hearing test of both ears. Of the 200 subjects, 63 displayed hearing loss associated with the RIPOR2 variant. 


In the first family studied, a segregation analysis uncovered the RIPOR2 variant in 20 of 23 affected subjects. The variant was also found in three unaffected family members aged 23, 40, and 51 years. 


The strong association of the variant with hearing loss in this family spurred the researchers to further address this and other variants in RIPOR2 in families with adult-onset hearing loss, according to the study.  


Further gene sequencing and the same general examinations were given to the other 11 families affected by hearing loss. The same genetic variant was found in 39 of 40 family members with hearing loss, but also in two people aged 49 and 50 who weren’t affected by hearing loss. The RIPOR2 variant was also present in the exomes of 18 of more than 22,000 unrelated individuals in a database from the Southeast Netherlands whose hearing status was unknown. Furthermore, there were four subjects with hearing loss who did not have the RIPOR2 variant. Their deafness suggests that it is associated with environmental factors, such as heavy smoking, or other genetic abnormalities, according to the researchers.   


Based on the audiometric phenotype and age of onset, hearing loss varied in individuals with the RIPOR2 variant. Five subjects with the variant had normal hearing and were aged 23, 40, 51, 49, and 50 years. Of the 12 families studied, the average reported age of hearing loss onset was just over 30 years, with the highest reported onset being 70 years of age. This suggests that the unaffected individuals may develop hearing loss in the future, although the researchers noted that the variant could be displaying incomplete penetrance.  


Even with these findings, the researchers did not find a clear pattern of age of onset or audiometric configurations observed within families with the RIPOR2 variant. These results may be an interplay between the environment and genetic modifying factors, they noted.  


It is likely that the RIPOR2 variant is the most common cause of hearing loss in the Netherlands and possibly surrounding countries, said Kremer. This variant's allele frequency (AF) suggests that it potentially explains adult-onset hearing loss in thousands of individuals in the Netherlands and northwest Europe, according to the study.  


The genetic defect that the team identified is relatively common, said Kremer, and is likely to explain more than 8,000 cases with hearing loss in the Netherlands. "Our findings show that ‘mild’ defects in genes known to be associated with severe, early-onset hearing impairment can be causative for adult-onset hearing impairment," said Kremer.  


The researchers' next steps are to study the molecular mechanisms that lead to hearing loss in mouse and zebrafish in order to develop a genetic therapy. The team also wants to find out if everyone with the RIPOR2 variant will develop hearing loss. "We want to identify genetic and/or environmental factors that might influence the age of onset as some individuals with the variant develop hearing loss before their twenties and others only after 40 years of age," said Kremer.