Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing Impairment.

Congenital hearing impairment is a sensory disorder that is genetically highly heterogeneous. By performing exome sequencing in two families with congenital nonsyndromic profound sensorineural hearing loss (SNHL), we identified autosomal dominantly inherited missense variants [p.(Asn283Ser); p.(Thr116Ile)] in , a neural crest regulatory molecule. The p.(Thr116Ile) variant was also associated with bilateral cochlear aplasia and cochlear nerve aplasia upon temporal bone imaging, an ultra-rare phenotype previously seen in patients with de novo variants. An important role of GREB1L in normal ear development has also been demonstrated by zebrafish, which show an abnormal sensory epithelia innervation. Last, we performed a review of all disease-associated variation described in , as it has also been implicated in renal, bladder and genital malformations. We show that the spectrum of features associated with is broad, variable and with a high level of reduced penetrance, which is typically characteristic of neurocristopathies. So far, seven variants (14%) have been associated with ear-related abnormalities. In conclusion, these results show that autosomal dominantly inherited variants in cause profound SNHL. Furthermore, we provide an overview of the phenotypic spectrum associated with variants and strengthen the evidence of the involvement of in human hearing.