Abstract
Autosomal dominant non-syndromic hearing loss (ADNSHL) displays gene-specific progression of hearing loss, which is amenable to sequential audioprofiling. We sought to refine the natural history of ADNSHL by examining audiometric data in 5-year increments. 2175 audiograms were included from four genetic causes of ADNSHL—KCNQ4 (DFNA2), GSDME (DFNA5), WFS1 (DFNA6/14/38), and COCH (DFNA9). Annual threshold deterioration (ATD) was calculated for each gene: for the speech-frequency pure tone average, the ATD, respectively, was 0.72 dB/year, 0.94 dB/year, 0.53 dB/year, and 1.41 dB/year, with the largest drops occurring from ages 45–50 (0.89 dB/year; KCNQ4), 5–10 (1.42 dB/year; GSDME), 40–45 (0.83 dB/year; WFS1), and 50–55 (2.09 dB/year; COCH). 5-year interval analysis of audiograms reveals the gene specific natural history of KCNQ4, GSDME, WFS1 and COCH-related progressive hearing loss. Identifying ages at which hearing loss is most rapid informs clinical care and patient expectations. Natural history data are also essential to define outcomes of clinical trials that test novel therapies designed to correct or ameliorate these genetic forms of hearing loss.
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Data availability
Data supporting this study’s findings are available within the article and its supplementary materials.
Code availability
Code used to generate 3-D audioprofile surfaces using the MathWorks MATLAB programming platform (Natick, MA) is publicly available at https://github.com/clcg/audioprofile-surfaces.
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Acknowledgements
This project was supported by National Institutes of Health—National Institute on Deafness and Other Communication Disorders grant R01 DC002842, DC012049 and DC017955 (RJHS) and National Institutes of Health—National Institute on Deafness and Other Communication Disorders grant 5T32DC000040 (RKT).
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RKT, TLC, and RJHS devised the project. RKT, WDW, RC, PH, TLC, and RJHS collected the data. RKT, WDW, RC, TLC, KW, and RJHS performed the calculations and analyzed the data. RKT and AS reviewed the included variants using the American College of Medical Genetics and Genomics (ACMG) criteria. RKT and RJHS wrote the manuscript. All authors discussed the results of the analysis and contributed to the final manuscript.
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Audiograms for AudioGene were collected from patients and data anonymized as approved by the University of Iowa Institutional Review Board (IRB), project identification number 199701065.
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439_2021_2424_MOESM1_ESM.xlsx
Supplementary file1 (XLSX 33 KB) Supplemental Table S1: Variants included in the database of audiograms with their associated ACMG (American College of Medical Genetics and Genomics) criteria, pathogenicity classification, in silico pathogenicity scores, minor allele frequencies, and protein domain. †: this variant is a complex rearrangement and thus ACMG variant criteria were not applied. COCH: NM_004086.3, KCNQ4: NM_004700.4, GSDME: NM_004403.2, WFS1: NM_006005.3, PP2 = PolyPhen-2, MT = MutationTaster, P = Pathogenic, LP = Likely Pathogenic, VUS = Variant of Uncertain Significance, ND = No Data, N/A: Not Applicable, D = Damaging, B = Benign, N = Neutral, C = Conserved, NC = Non-Conserved. Supplemental Table S2: Number of families, audiograms per family, and reported ethnicity and country of origin for each variant included in this study. Multiple rows are used for single variants if there are audiograms from multiple ethnicities for that variant. The source of the audiogram is also reported as from AudioGene, OtoSCOPE (a comprehensive massively parallel sequencing panel for hearing loss), or a separate manuscript’s PMID (PubMed reference number). Supplemental Table S3: 2nd- and 3rd-order polynomial root mean square error (RMSE) values for each value of dB hearing level for each gene at 250, 500, 1000, 2000, 4000, and 8000 Hz. Supplemental Table S4: Annual threshold deterioration (ATD) at each frequency and at the speech pure tone average (the average of 500, 1000, 2000, and 4000 Hz) for each gene and each available age bin, in dB/year.
439_2021_2424_MOESM2_ESM.tif
Supplementary file2 (TIF 385 KB) Supplemental Figure S1: Three-dimensional audioprofile surfaces of KCNQ4 (DFNA2) (A), GSDME (DFNA5) (B), WFS1 (DFNA6/14/38) (C), and COCH (DFNA9) (D) are fitted to third degree polynomials, with frequency in the x-axis, decibel hearing level on the y-axis, and age in the z-axis
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Thorpe, R.K., Walls, W.D., Corrigan, R. et al. AudioGene: refining the natural history of KCNQ4, GSDME, WFS1, and COCH-associated hearing loss. Hum Genet 141, 877–887 (2022). https://doi.org/10.1007/s00439-021-02424-7
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DOI: https://doi.org/10.1007/s00439-021-02424-7