| Summary: | 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 <i>GREB1L</i>, 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 <i>GREB1L</i> variants. An important role of GREB1L in normal ear development has also been demonstrated by <i>greb1l</i><sup>−/−</sup> zebrafish, which show an abnormal sensory epithelia innervation. Last, we performed a review of all disease-associated variation described in <i>GREB1L</i>, as it has also been implicated in renal, bladder and genital malformations. We show that the spectrum of features associated with <i>GREB1L</i> is broad, variable and with a high level of reduced penetrance, which is typically characteristic of neurocristopathies. So far, seven <i>GREB1L</i> variants (14%) have been associated with ear-related abnormalities. In conclusion, these results show that autosomal dominantly inherited variants in <i>GREB1L</i> cause profound SNHL. Furthermore, we provide an overview of the phenotypic spectrum associated with <i>GREB1L</i> variants and strengthen the evidence of the involvement of <i>GREB1L</i> in human hearing.
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