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)] inGREB1L, 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 novoGREB1Lvariants. An important role of GREB1L in normal ear development has also been demonstrated bygreb1l(-/-)zebrafish, which show an abnormal sensory epithelia innervation. Last, we performed a review of all disease-associated variation described inGREB1L, as it has also been implicated in renal, bladder and genital malformations. We show that the spectrum of features associated withGREB1Lis broad, variable and with a high level of reduced penetrance, which is typically characteristic of neurocristopathies. So far, sevenGREB1Lvariants (14%) have been associated with ear-related abnormalities. In conclusion, these results show that autosomal dominantly inherited variants inGREB1Lcause profound SNHL. Furthermore, we provide an overview of the phenotypic spectrum associated withGREB1Lvariants and strengthen the evidence of the involvement ofGREB1Lin human hearing.

Jaar van publicatie:2020

Trefwoorden:A1 Journal article

BOF-keylabel:ja

BOF-publication weight:1

CSS-citation score:2

Auteurs:International

Authors from:Higher Education

Toegankelijkheid:Open