Genetic screening of LOXHD1 variants guides early hearing loss intervention

Hearing loss is a common cause of disability worldwide, with anywhere between 30-60% of cases being caused by genetic factors. LOXHD1 is a gene integral to essential protein interactions responsible for maintaining normal hair cell function. Certain variants in this gene can cause progressive or non-progressive congenital hearing impairments, called "pathogenic variants" in individuals. Researchers went deeper into this gene to learn more about the genetic causes of hearing loss in the Chinese population, and they uncovered novel variants within this gene to further explore these causes, in addition to what early intervention and potential medicinal therapies might look like for those who are predisposed to hearing loss.

Researchers published their results in the Journal of Otology (https://doi.org/10.26599/JOTO.2026.9540055) in April 2026.

157 individuals with hearing loss and their families were part of this study. 60.51% of affected individuals (95 patients) had potential causal variants, most frequently seen in the SLC26A4 and GJB2 genes. Further analysis revealed 10 different variants within the LOXHD1 gene, with five novel ones being linked to hearing loss. This information unveils even more of the known mutation spectrum of the LOXHD1 gene and points to its significance in auditory function, making understanding the mechanisms of mutation an important part of getting to the root cause of genetic hearing loss.

These variants have been found to significantly contribute to non-syndromic hearing loss, a type of hearing impairment that is hereditary, with hearing loss being the sole symptom.

Variants in the gene can result from different types of mutations affecting the protein, such as misfolding or frameshift mutations, which can lead to substitutions in the amino acid sequence. These substitutions can lead to early termination of protein translation, an essential step in the sequence of events that create functional proteins. The stability and performance of these proteins can also be drastically affected when incorrect amino acids are present. 

With this information, genetic screening becomes paramount to early intervention and establishing therapeutic options. Two patients received cochlear implants, one at the age of 10 months and the other at the age of 10 years, and were re-evaluated after 12 months. Results from the speech-language evaluation demonstrated expressive language development and auditory reception consistent with the patient's age, showing the benefit of genomic sequencing and early intervention for non-syndromic hearing loss. Genomic sequencing especially can be particularly insightful in cases where cochlear implants are considered for guiding operative decisions and post-operative effects.

The next step is to functionally characterize these novel LOXHD1 variants to understand how they disrupt hearing at the molecular level."

Kun Zhang, researcher at Qilu Hospital of Shangdong University and author of the study

With favorable outcomes in the two young patients and momentum gained in understanding LOXHD1 variants, researchers hope to use the knowledge found in this study to continue their work on establishing genetic variants in the LOXHD1 gene. Developing precise genetic tests can lead to personalized interventions for patients with hearing loss, and expanding upon this research can improve the quality of life for many people across the globe.

Kun Zhang, Xijian Xin, Shiqi Huang, Bo Hou, Xinbo Xu, Xiao Han and Hanbing Zhang of the Department of Otorhinolaryngology at the Qilu Hospital of Shangdong University and the NHC Key Laboratory of Otorhinolaryngology at Shangdong University, and Peng Qu of the Dermatology Hospital of Shangdong First Medical University and Shangdong Provincial Institute of Dermatology and Venerology at the Shangdong Academy of Medical Sciences contributed to this research.

The Natural Science Foundation of Shangdong Province supported this research.