Suzanne de Bruijn

107 A RIPOR2 deletion is a frequent cause of adult-onset hearing loss The mean reported age of onset is 30.6 years (standard deviation 14.9 years) with a wide range from congenital to 70 years ( Figure S4 ). Evaluation of audiometric data showed that subjects with the RIPOR2 variant have progressive sensorineural HL, ranging from mild to profound, with variable audiometric configurations ( Figure 3 , Figure S5 ). In order to distinguish audiometric patterns, a k-means clustering algorithm, independent of subject age, was applied on the latest audiogram of each subject. This unbiased approach yielded four audiometric patterns, each with a distinct audiometric configuration ( Figure 4 ). Asymmetry of HL was seen in 16 cases. Inter-aural differences in progression of HL were also seen ( Figure 3C ). For three subjects (III:30 of family W97- 056, II:11 of family W04-262 and V:1 of W08-1421), an explanation for asymmetry was noted ( Table S3 ). 0 40 80 60 20 100 120 -10 dB .25 .5 1 2 4 8 W97-056 IV:20 6.5 y 15.4 y 29.4 y 39.4 y p95 (51 y) 50.9 y Hearing threshold (dB HL) 0 40 80 60 20 100 120 -10 .25 .5 1 2 4 8 W04-262 III:5 49.2 y 62.5 y p95 (63 y) dB kHz 0 40 80 60 20 100 120 -10 dB .25 .5 1 2 4 8 kHz W97-056 IV:28 24.7 y L p95 (46 y) 45.6 y L 24.7 y R 45.6 y R Frequency (kHz) Hearing threshold (dB HL) .25 .5 1 2 4 8 0 100 120 80 60 40 20 ARTA 10 20 30 60 40 50 70 dB kHz Frequency (kHz) y kHz A D C B Hearing threshold (dB HL) Hearing threshold (dB HL) Frequency (kHz) Frequency (kHz) Figure 3. Selection of audiograms and the ARTA. (A-C) Air conduction thresholds of three selected individuals with the c.1696_1707del RIPOR2 variant are depicted. For the individuals in panels A and B, hearing loss was symmetric and the average of left and right ear thresholds are depicted. For the individual in panel C, hearing loss was asymmetric and the thresholds for both right and left ears are depicted. The p95 values are matched to the individuals’ sex and age at most recent audiometry, according to the ISO 7029:2017 standard. ( D) Age Related Typical Audiogram (ARTA), cross-sectional linear regression analysis of last visit audiograms of affected subjects with the c.1696_1707del RIPOR2 variant. y, age in years; R, right; L, left; dB HL, decibel hearing level; kHz; kiloHertz