The natural history, clinical outcomes, and genotype-phenotype relationship of otoferlin-related hearing loss: a systematic, quantitative literature review

Abstract

Congenital hearing loss affects one in 500 newborns. Sequence variations in OTOF, which encodes the calcium-binding protein otoferlin, are responsible for 1-8% of congenital, nonsyndromic hearing loss and are the leading cause of auditory neuropathy spectrum disorders. The natural history of otoferlin-related hearing loss, the relationship between OTOF genotype and hearing loss phenotype, and the outcomes of clinical practices in patients with this genetic disorder are incompletely understood because most analyses have reported on small numbers of cases with homogeneous OTOF genotypes. Here, we present the first systematic, quantitative literature review of otoferlin-related hearing loss, which analyzes patient-specific data from 422 individuals across 61 publications. While most patients display a typical phenotype of severe-to-profound hearing loss with prelingual onset, 10-15% of patients display atypical phenotypes, including mild-to-moderate, progressive, and temperature-sensitive hearing loss. Patients' phenotypic presentations appear to depend on their specific genotypes. For example, non-truncating variants located in and immediately downstream of the C₂E calcium-binding domain are more likely to produce atypical phenotypes. Additionally, the prevalence of certain sequence variants and their associated phenotypes varies between populations due to evolutionary founder effects. Our analyses also suggest otoacoustic emissions are less common in older patients and those with two truncating OTOF variants. Critically, our review has implications for the application and limitations of clinical practices, including newborn hearing screenings, hearing aid trials, cochlear implants, and upcoming gene therapy clinical trials. We conclude by discussing the limitations of available research and recommendations for future studies on this genetic cause of hearing loss.

Fig. 1

Data collection flow diagram. From the 111 publications identified in our initial database search, we analyzed patient-specific data on 422 cases with biallelic OTOF variants across 61 publications, in addition to group data from one publication. OAE otoacoustic emissions, NBHS newborn hearing screening

Fig. 2

Phenotypes. The spectrum of reported phenotypes in otoferlin-related sensorineural hearing loss (A) was subdivided into phenotypes classified with behavioral audiometry (B), electrophysiological audiometry (C), and audiometry with unspecified methodology (D). The phenotypes of cases with absent auditory brainstem responses (ABRs) at the maximum stimulation tested are shown in (E) while the phenotypes of cases with abnormal ABRs are shown in (F). Phenotype classification was assigned based on hearing thresholds as follows: 0–25 dB, normal; 26–40 dB, mild; 41–70 dB, moderate; 71–90 dB, severe; > 90 dB, profound. NT non-truncating, T truncating

Fig. 3

Phenotypes by age. The distribution of hearing phenotypes reported in patients of different ages is shown. The majority of cases in all age groups have severe-to-profound sensorineural hearing loss. The relative paucity of temperature-sensitive, mild, and moderate cases at younger ages is likely a consequence of delayed diagnoses rather than a physiological process. Unstable and progressive cases were omitted due to their variability over time. Year of Life 1 = birth to 1 year old; Year of Life 2 = 1.01 years old to 2 years old; etc.

Fig. 4

Phenotypes by genotype. The spectrum of phenotypes in cases with biallelic OTOF variants was subdivided according to genotype. Twenty-two percent of cases with two non-truncating alleles (NT/NT) had atypical (mild, moderate, temperature-sensitive, progressive, or unstable) phenotypes (A). Atypical phenotypes were present in 14% of cases with one non-truncating and one truncating allele (NT/T; B), and in 2.7% of cases with two truncating alleles (T/T; C). Hearing thresholds: 0–25 dB, normal; 26–40 dB, mild; 41–70 dB, moderate; 71–90 dB, severe; > 90 dB, profound

Fig. 5

Phenotypes by non-truncating variant. A Shows a schematic of otoferlin with specific domains demarcated and the locations of common non-truncating (NT) alleles. B Shows each reported instance of a NT allele within each gene region, as well as the phenotype of the patient, such that the phenotypes of cases with two NT alleles are represented twice (once for each allele) and the phenotypes of cases with one NT allele and one truncating allele are represented once. Pathogenic NT variants were frequently reported in some regions (e.g., C₂F, C₂F-TM) and not reported in others (e.g., C₂A, FerB), and NT variants were more commonly associated with atypical phenotypes in some regions (e.g., C₂E) than in others (e.g., C₂F-TM). C Shows the most common NT alleles in our dataset and their associated phenotypes (each allele is represented once, so the phenotypes of homozygous cases are represented twice). Variant p.I1573T is notable for its frequent association with mild-to-moderate sensorineural hearing loss, whereas p.E1700Q is commonly associated with progressive or temperature-sensitive sensorineural hearing loss. C₂A, C₂B, C₂C, C₂D, C₂E, and C₂F C₂ domains, C₂de putative C₂ domain, FerA FerB ferlin domains, TM transmembrane domain

Fig. 6

Otoacoustic emissions. Otoacoustic emissions (OAEs) were present, present but reduced, or initially present and lost over time in over 80% of cases (A). The proportion of cases with present OAEs decreases in older age groups (B; n = 5 cases with OAEs that were initially present and lost over time are represented twice, once at their oldest age with present OAEs and once at their youngest age with absent OAEs). Patients with mild or temperature-sensitive sensorineural hearing loss were more likely to have present OAEs than patients with other phenotypes (C), and patients with at least one non-truncating (NT) allele were more likely to have present OAEs than patients with two truncating (T) alleles (D). Only hearing loss phenotypes classified using behavioral audiometry were included in C. Year of Life 1 = birth to 1 year old; Year of Life 2 = 1.01 years old to 2 years old; etc.

Fig. 7

Otoacoustic emissions by age and phenotype or genotype. The age in years and results of otoacoustic emission (OAE) testing are shown for individuals with mild (A), moderate (B), severe (C), and profound (D) sensorineural hearing loss, and for individuals with two non-truncating (NT) alleles (E), one NT and one truncating (T) allele (F), and two T alleles (G). Individuals with reduced OAEs are represented as gray dots in the “Present” column, and individuals with present OAEs at one time and absent OAEs at a later time are represented twice, once in the “Present” and once in the “Absent” column, with blue dots. Red lines indicate the median age. Only hearing loss phenotypes classified using behavioral audiometry were included in A–D

Fig. 8

Newborn hearing screening outcomes. The results of auditory brainstem response (ABR)-based and otoacoustic emission (OAE)-based newborn hearing screenings (NBHS), as well as those with unspecified methodology, are shown. Twenty-three of 24 (96%) OAE-based NBHS were inappropriately passed compared to three of 35 (8.6%) ABR-based tests. Two patients underwent both OAE-based and ABR-based screening and are represented once in both the OAE and ABR columns; both patients passed the OAE test and failed the ABR test