Distinct genetic patterns and natural history of OPA1-related auditory neuropathy in Chinese population

Auditory neuropathy (AN) represents a clinical manifestation of OPA1-related diseases. The diagnostic process of these diseases is challenging owing to the broad spectrum of intermediate phenotypes and diverse inherited patterns. The aim of this study was to comprehensively delineate the feature of OPA1-related patients in a Chinese AN cohort, encompassing the incident rate, inherited pattern, detailed audiological characteristics, and genotype-phenotype correlation.

Between 2003 and 2020, 452 unrelated probands with a diagnosis of AN were referred to our laboratory for molecular genetic investigation with high-throughput sequencing. Sanger sequencing was performed on the probands and their parents to verify the genetic results. Patients diagnosed as AN by clinical evaluation, auditory brainstem responses, otoacoustic emission and/or cochlear microphonic. Comprehensive auditory evaluations were conducted on OPA1-related patients, and some of them were performed a follow-up study.

We identified seven probands (1.55%, 7/452) with OPA1 variants in seven unrelated families, demonstrating distinct genetic patterns, including one family with rare autosomal recessive (AR) inheritance, six families with autosomal dominant (AD) inheritance (three were AD de novo). The AN phenotype was observed in all patients prior to the second decade of life, with AN serving as the initial presenting symptom in two patients. Additionally, probands with the rare AR inheritance exhibited a more severe phenotype. A total of eight OPA1 variants were identified, including a novel variant c.2013 + 5G > C. The GTPase domain of OPA1 exclusively harbored missense variants, and 85.71% (6/7) of the patients carried one of missense variants in OPA1. The observed phenotypes exhibited a broad spectrum of manifestations, encompassing vestibular dysfunction and developmental delay, with varying degrees of hearing loss. Among the seven patients, four exhibited severe to profound hearing loss. The annual rates of hearing loss at the frequencies of speech were 2.74 dB/year for one patient, who underwent a 10-year-old follow-up.

Our results indicated the distinct genetic patterns and variable phenotypic characteristics of OPA1-related AN in the Chinese population. The audiological features of OPA1-related patients were comprehensively described as exhibiting AN. We identified one novel splicing variants that expand the genetic spectrum of OPA1 variants in AN.