NIH
Zebra of the Week: OTOF-Related Genetic Deafness (DFNB9)
Autosomal recessive nonsyndromic hearing loss 9 (DFNB9) is a rare genetic condition caused by mutations in the OTOF gene, which encodes otoferlin. This disorder primarily affects hearing and is inherited in an autosomal recessive pattern, requiring pathogenic variants in both gene copies.
DFNB9 includes two principal clinical phenotypes. The first is prelingual nonsyndromic auditory neuropathy spectrum disorder (ANSD), in which individuals are typically born with severe-to-profound deafness despite the absence of structural abnormalities in the inner ear. The second, less common form is temperature-sensitive ANSD (TS-ANDS), characterized by baseline normal-to-moderate hearing that can acutely worsen with even small increases in body temperature, with subsequent return to baseline.
A key diagnostic feature is the dissociation between cochlear and neural function. Patients may demonstrate preserved otoacoustic emissions alongside abnormal auditory brainstem responses, reflecting impaired transmission of sound signals from inner hair cells to the auditory nerve. Importantly, because of this mechanism, standard newborn screening that relies solely on otoacoustic emissions may fail to detect the disorder, contributing to delayed diagnosis.
Pathophysiologically, otoferlin is essential for synaptic signaling within the cochlea; mutations disrupt neurotransmitter release from inner hair cells, preventing effective auditory signal transmission to the brain.
Management has traditionally focused on early identification and auditory rehabilitation, including hearing aids and cochlear implantation when appropriate, along with early language and educational support.
In April 2026, FDA approved Otarmeni (lunsotogene parvec‑cwha), the first gene therapy for OTOF-related hearing loss—representing a shift toward disease-modifying treatment.
Source: Genetic and Rare Diseases Information Center (GARD). Autosomal recessive nonsyndromic hearing loss 9. National Institutes of Health.