Genotype-phenotype Correlation Study in a Large Series of Patients Carrying the p.Pro51Ser (p.P51S) Variant in COCH (DFNA9): Part I-A Cross-sectional Study of Hearing Function in 111 Carriers

Sebastien P F JanssensdeVarebeke, Julie Moyaert, Erik Fransen, Britt Bulen, Celine Neesen, Katrien Devroye, Raymond van de Berg, Ronald J E Pennings, Vedat Topsakal, Olivier Vanderveken, Guy Van Camp, Vincent Van Rompaey, Sebastien P F JanssensdeVarebeke, Julie Moyaert, Erik Fransen, Britt Bulen, Celine Neesen, Katrien Devroye, Raymond van de Berg, Ronald J E Pennings, Vedat Topsakal, Olivier Vanderveken, Guy Van Camp, Vincent Van Rompaey

Abstract

Introduction: DFNA9 is characterized by adult-onset progressive sensorineural hearing loss (SNHL) and vestibular impairment. More than 15 years ago, genotype-phenotype correlation studies estimated the initial age of hearing deterioration in the fourth to fifth decade (ranging from 32 to 43 years). However, these analyses were based on relatively limited numbers of mainly symptomatic carriers using markedly different methodologies. The starting point for the hearing deterioration is more correctly determined with larger numbers of carriers and with a more clearly defined starting point of the hearing deterioration.

Aim: The aim of this study was to determine milestone ages (start and maximal hearing deterioration, potential eligibility for hearing aids and cochlear implants based on pure-tone average [PTA]) in a large series of p.Pro51Ser COCH variant carriers. The degree of individual interaural asymmetry and the degree of variability (interquartile range) with which the hearing deterioration progresses across ages were also studied, and age-related typical audiograms (ARTA) were constructed.

Material and methods: One hundred eleven Belgian and Dutch p.P51S variant carriers were identified and recruited for audiological investigation. Their hearing thresholds were compared with p50th, p95th, and p97.5th percentile values of presbyacusis (ISO 7029 standards). The onset and degree of hearing deterioration were defined and assessed for each frequency and with three PTAs (PTA0.5-4 [0.5, 1, 2, and 4 kHz]; PTA4-8 [4 and 8 kHz]; and PTA6-8 [6 and 8 kHz]). The milestones ages were derived from nonlinear regression model of hearing thresholds against age, for male and female carriers separately, because of different age-referenced limits. Interaural right-left asymmetry was assessed, and variability of hearing thresholds were calculated using interquartile range. ARTAs were built with both observed data and a prediction model.

Results: Hearing dysfunction in p.P51S carriers begins at about 38 years of age (ranging from 28 to 43 years) on average in female and 46 years (ranging from 42 to 49 years) in male carriers (third decade: female, fifth decade: male carriers), depending on the hearing frequency and with differences in deterioration sequence between both genders. These differences, however, were mainly due to more stringent age-referenced limits for men. In contrast, predictions (ARTA) did not show any difference of phenotypic expression between genders. At about 48 to 50 years of age on average, the majority of DFNA9 patients may need conventional hearing aids (PTA ≥ 40 dB HL), whereas this is about 56 to 59 years for cochlear implants (PTA ≥ 70 dB HL). There is a high degree of individual interaural asymmetry and interindividual variability throughout all ages.

Conclusion: This study demonstrates that the onset of sensorineural hearing deterioration starts in the third decade and probably even earlier. Regardless of differences in estimates, DFNA9 expresses similarly in male and female carriers, but male carriers are much more difficult to identify in early stages of the disease. Comprehensive assessment of the natural course of DFNA9 is of particular interest to predict the age of onset or critical period of most significant function deterioration in individual carriers of the pathogenic variant. This will help to design studies in the search for disease-modifying therapies.

Trial registration: ClinicalTrials.gov NCT03716908.

Conflict of interest statement

There are no conflicts of interest to declare.

Copyright © 2021 The Authors. Ear & Hearing is published on behalf of the American Auditory Society, by Wolters Kluwer Health, Inc.

Figures

Fig. 1.
Fig. 1.
A, B, Hearing thresholds of 5 (10 ears) p.P51S variant carriers aged in the third decade in relation to the corresponding p50th, p95th, and p97.5th percentile values for presbyacusis, for male (A) and female carriers (B). Note that (A) only represents data from one subject. The upper and lower borders of the boxes represent 25th and 75th quartiles, respectively. The boxes contain 50% of the values and represent the IQR. The bold horizontal lines in the boxes are the medians (asterix [*]: the mean value of the hearing thresholds of corresponding decade is significantly greater than corresponding age-referenced limit [ISO 7029]). IQR, interquartile range.
Fig. 2.
Fig. 2.
A, B, Hearing thresholds of 16 (32 ears) p.P51S variant carriers aged in the fourth decade in relation to the corresponding p50th, p95th, and p97.5th percentile values for presbyacusis, for male (A) and female carriers (B). The upper and lower borders of the boxes represent 25th and 75th quartiles, respectively. The boxes contain 50% of the values and represent the IQR. The bold horizontal lines in the boxes are the medians (asterix [*]: the mean value of the hearing thresholds of corresponding decade is significantly greater than corresponding age-referenced limit [ISO 7029]). IQR, interquartile range.
Fig. 3.
Fig. 3.
A, B, Hearing thresholds of 21 (42 ears) p.P51S variant carriers aged in the fifth decade in relation to the corresponding p50th, p95th, and p97.5th percentile values for presbyacusis, for male (A) and female carriers (B). The upper and lower borders of the boxes represent 25th and 75th quartiles, respectively. The boxes contain 50% of the values and represent the IQR. The bold horizontal lines in the boxes are the medians (asterix [*]: the mean value of the hearing thresholds of corresponding decade is significantly greater than corresponding age-referenced limit [ISO 7029]). IQR, interquartile range.
Fig. 4.
Fig. 4.
Frequency-specific progression of hearing thresholds in 54 male p.P51S variant carriers in function of their age (108 ears). Note that hearing loss starts earlier with higher frequencies, whereas there is a constant offset hearing threshold at lower frequencies which lies within range of normative values for 0.125 to 4 kHz.
Fig. 5.
Fig. 5.
Frequency-specific progression of hearing thresholds in 57 female p.P51S variant carriers in function of their age (114 ears). Note that hearing loss starts earlier with higher frequencies, whereas there is a constant offset hearing threshold at lower frequencies which lies within range of normative values for 0.125 to 3 kHz.
Fig. 6.
Fig. 6.
Interaural hearing threshold difference (dB HL) at all frequencies (0.125 to 8 kHz) in 21 P51S carriers (42 ears) (male and female) aged from 18 to 39 years. Note the higher level of threshold difference at highest frequencies (dotted line = 10 dB interaural difference).
Fig. 7.
Fig. 7.
Interaural hearing threshold difference (dB HL) at all frequencies (0.125 to 8 kHz) in 43 P51S carriers (86 ears) (male and female) aged from 40 to 59 years. Note the high level of threshold differences across all frequencies (dotted line = 10 dB interaural difference).
Fig. 8.
Fig. 8.
Interaural hearing threshold difference (dB HL) at all frequencies (0.125 to 8 kHz) in 47 P51S carriers (94 ears) (male and female) aged from 60 to 80 years. Note the higher level of threshold differences at lower frequencies (dotted line = 10 dB interaural difference).
Fig. 9.
Fig. 9.
ARTA based on observed data from 54 male (A) and 57 female (B) p.P51S carriers (observed ARTA).
Fig. 10.
Fig. 10.
Predicted ARTA derived from nonlinear dose-response regression model for male (A) and female (B) p.P51S carriers with corresponding 95% confidence intervals.

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