Founder variant in OTOG causing non-syndromic sensorineural hearing loss in Irish traveller population

Deafness is a common multifactorial sensory disorder with numerous underlying causes (genetic, environmental) and a broad range of impact on humans. To date, 156 non-syndromic hearing loss-associated genes have been identified (DFN) and 75%–80% follow a recessive inheritance pattern (DFNB). OTOG (MIM: 604487, chr11:17,547,259-17,646044, GrCh38) encodes otogelin, a non-collagenous protein specific to the inner ear tectorial membrane. Biallelic pathogenic variants in OTOG result in mild to moderate autosomal recessive non-syndromic SNHL (DNF18B). To date, only 41 families (63 individuals) have been reported in the literature. We report an additional seven families from the Irish Traveller population (16 individuals), with a recurrent homozygous variant in OTOG (c.3700C>T; p.Arg1234*) causing non-syndromic early-onset SNHL. The median current age is 9.5 years (IQR: 5.75–14.5 years). Two-thirds (n=11) were identified after failing newborn hearing screening, with others referred due to speech delay. All individuals have mild to moderate SNHL, with a characteristic U-shaped or ‘cookie bite’ audiogram. Similar to previously reported cases of OTOG- associated SNHL, in our cohort, SNHL was non-progressive even in our adult patients. There were no features of vestibular dysfunction or neurodevelopmental impairment. We reviewed all reported cases to date, in addition to our families (n=79). We demonstrate that protein-truncating variants are scattered throughout the length of the OTOG protein. However, pathogenic missense variants occur only in key domains such as vWD and trypsin inhibitor-like cysteine-rich domains. This report highlights a founder variant in OTOG within the Irish Traveller population. Clinicians should ensure that this is requested in all infants who fail newborn screening from this ethnicity.