Cochleovestibular fragility: the human and murine 22q11.2DS model

The 22q11 deletion syndrome (22q11DS) is the most common chromosomal microdeletion syndrome, characterized mainly by various degrees of congenital heart disease, cleft palate or velopharyngeal insufficiency and learning difficulties. Hearing loss has usually been attributed to chronic middle ear disease based on dysfunction of the Eustachian tube and the aberrant anatomy and function of the palatal musculature, but recent research also shows an unexplained high rate of sensorineural hearing loss and indications for cochlear damage. Furthermore, a first screening of the vestibular function in these patients demonstrated a high prevalence of abnormal equilibrium. Through these insights, we propose the new concept of cochleovestibular fragility, referring to an increased vulnerability of the inner ear function in 22q11DS. As such, environmental factors such as high-level noise exposure or middle ear infection lead to damage of the inner ear with sensorineural hearing loss, with a higher susceptibility than we would expect when compared to a healthy population. We will investigate this hypothesis both by performing human clinical studies and by innovative fundamental research in a mouse model of 22q11DS. This will provide us with a unique insight into the multifactorial pathophysiology of cochleovestibular abnormalities in 22q11DS, and will guide future management of otovestibular disorders in these patients. We intend to develop an audiovestibular assessment tool in mice, which will also prove very valuable in characterizing the inner ear function in other pathologies, especially in the light of the growing interest in phenotype-genotype correlation research.