Association of Genetic Diagnoses for Childhood-Onset Hearing Loss With Cochlear Implant Outcomes

Abstract

Importance: In the US, most childhood-onset bilateral sensorineural hearing loss is genetic, with more than 120 genes and thousands of different alleles known. Primary treatments are hearing aids and cochlear implants. Genetic diagnosis can inform progression of hearing loss, indicate potential syndromic features, and suggest best timing for individualized treatment.

Objective: To identify the genetic causes of childhood-onset hearing loss and characterize severity, progression, and cochlear implant success associated with genotype in a single large clinical cohort.

Design, setting, and participants: This cross-sectional analysis (genomics) and retrospective cohort analysis (audiological measures) were conducted from 2019 to 2022 at the otolaryngology and audiology clinics of Seattle Children's Hospital and the University of Washington and included 449 children from 406 families with bilateral sensorineural hearing loss with an onset younger than 18 years. Data were analyzed between January and June 2022.

Main outcomes and measures: Genetic diagnoses based on genomic sequencing and structural variant analysis of the DNA of participants; severity and progression of hearing loss as measured by audiologic testing; and cochlear implant success as measured by pediatric and adult speech perception tests. Hearing thresholds and speech perception scores were evaluated with respect to age at implant, months since implant, and genotype using a multivariate analysis of variance and covariance.

Results: Of 406 participants, 208 (51%) were female, 17 (4%) were African/African American, 32 (8%) were East Asian, 219 (54%) were European, 53 (13%) were Latino/Admixed American, and 16 (4%) were South Asian. Genomic analysis yielded genetic diagnoses for 210 of 406 families (52%), including 55 of 82 multiplex families (67%) and 155 of 324 singleton families (48%). Rates of genetic diagnosis were similar for children of all ancestries. Causal variants occurred in 43 different genes, with each child (with 1 exception) having causative variant(s) in only 1 gene. Hearing loss severity, affected frequencies, and progression varied by gene and, for some genes, by genotype within gene. For children with causative mutations in MYO6, OTOA, SLC26A4, TMPRSS3, or severe loss-of-function variants in GJB2, hearing loss was progressive, with losses of more than 10 dB per decade. For all children with cochlear implants, outcomes of adult speech perception tests were greater than preimplanted levels. Yet the degree of success varied substantially by genotype. Adjusting for age at implant and interval since implant, speech perception was highest for children with hearing loss due to MITF or TMPRSS3.

Conclusions and relevance: The results of this cross-sectional study suggest that genetic diagnosis is now sufficiently advanced to enable its integration into precision medical care for childhood-onset hearing loss.

Figure 1.. Genetic Diagnoses for Participants, With Variants in 43 Genes

A, Genes responsible for hearing loss (HL) for the 210 families with genetic diagnoses (of 406 families total). B, Number of families with and without genetic diagnoses for singleton vs multiplex families, nonsyndromic vs syndromic hearing loss based on clinical presentation, and probands with mild/moderate or severe/profound hearing loss.

Figure 2.. Variation in Audiogram Thresholds by Gene, Genotype, and Age

A, For children with GJB2-related hearing loss, hearing thresholds averaged across all ages for children with 3 classes of GJB2 genotypes: 2 missense variants (miss/miss), 1 truncation and 1 missense variant (TR/miss), and 2 truncating variants (TR/TR). B, Age-specific hearing thresholds by causative gene, and for GJB2 by genotype. All tests were unaided (ie, without use of hearing aids or cochlear implants). Bone conduction was substituted for air conduction when available. Results for each ear are included separately. For each panel, n indicates the number of participants with audiometric data. Error bars indicate SEM. Thresholds for several genes suggest progressive hearing loss (see Figure 3 for details). Definitions of gene names and plots for additional genes appear in supplementary data.

Figure 3.. Significance of Progression by Age for Children With Hearing Losses Due to GJB2, MYO6, OTOA, SLC26A4, and TMPRSS3

A, Pure tone averages (PTAs) of hearing thresholds at 500, 1000, 2000, 4000 Hz were plotted by age at test. Only ears that never received cochlear implants were included. Hearing loss progressed significantly by age for children with variants in MYO6, OTOA, SLC26A4, and TMPRSS3 or with 2 truncating variants (TR/TR) in GJB2. B, Progression of TMPRSS3-related hearing loss at each frequency for 3 classes of TMPRSS3 genotypes: 2 missense variants (miss/miss), compound heterozygosity for a frameshift and a missense variant (fs/miss), and 2 frameshift variants (fs/fs). For fs/miss and miss/miss genotypes, only ears that never received cochlear implants were included. All participants with fs/fs genotypes received bilateral implants before age 3 years, and their preimplant results are included for comparison with other genotypes. At 250 and 500 Hz, the rate of progression (slope) varied significantly by genotype. Data for individual tests are in eTables 4 and 5 in Supplement 1.

Figure 4.. Association of Variation in Cochlear Implant Outcomes With Underlying Genotype

A, Maximum scores for adult-level speech perception tests, CNC (words) and AzBio (Quiet), for each individual with a cochlear implant as separated by causative gene. B, Speech perception scores by gene. Scores for each test (HINT-C, Pediatric AzBio, AzBio, PBK, and CNC) were converted to z scores by comparison with the mean for that test. For each participant, the best score for each test was included. Box plots represent 25%, 50%, and 75% percentiles. After adjusting for age at implant and time between implant and testing, scores for participants with variants in MITF or TMPRSS3 were higher than average and for the participant with variants in GPSM2 were lower than average (blue boxes) (eTable 6B in Supplement 1). The child with GPSM2 hearing loss had a syndromic presentation, including developmental delay. C, There were no significant differences by genotype for participants with variants in GJB2 or TMPRSS3. None of the patients with 2 GJB2 missense variants had cochlear implants.