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

Abstract

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

Keywords: GREB1L; autosomal dominant inheritance; cochlear aplasia; cochlear nerve aplasia; exome sequencing; neural crest; neurocristopathy; profound nonsyndromic hearing impairment.

Figure 1

Segregation of the GREB1L missense variants in both families, audiological and imaging data. A/B. Segregation of the p.(Asn283Ser) GREB1L variant in family 1 (4697) (A) and p.(Thr116Ile) variant in family 2 (BAIE1) (B). Solid black symbols represent affected individuals and clear symbols unaffected family members. Grey symbols represent unaffected individuals that are also heterozygous for the variant (reduced penetrance). Females are represented by circles and males by squares. (C) Pure-tone audiograms of hearing-impaired family members of family 1 illustrate that each one presents with bilateral profound HI. (D) Oblique sagittal T2 sequence across the right internal auditory canal (IAC) of patient II:1 of family 2. The white arrow indicates the vestibular nerve (black dot). The arrowhead indicates a hypoplastic facial nerve (small grey dot). The black arrow indicates the area in the IAC where the cochlear nerve is expected but not observed. (E) Maximum intensity projection of a heavily T2 weighted sequence to the inner ear of the affected individual (II:1) of family 2. Bilateral cochlear aplasia and dysplasia of the vestibular system is visualized. The white arrowhead indicates the area where the cochlea is expected but not seen (bilaterally). The white arrow indicates a dysplastic cystic dilated vestibule on each side. The black arrow indicates a left narrow IAC and the right broad IAC with wide communication between the fundus of the IAC and the vestibule. The black arrowhead indicates a right dilated lateral semicircular canal. The grey arrow indicates a right rudimentary posterior semicircular canal. L, Left; R, right.

Figure 2

All variants reported in GREB1L and their associated phenotypic features. A. GREB1L protein structure with all variants indicated. The seven bottom variants are associated with ear-related abnormalities. Dark green, TAGT or Ten-eleven translocation/J binding protein (TET/JBP)-associated glycosyltrasferase domain [39]. B. The percentage (%) of variants associated with the most prevalent phenotypic features seen in affected individuals.