A novel autosomal dominant GREB1L variant associated with non-syndromic hearing impairment in Ghana

Abstract

Background: Childhood hearing impairment (HI) is genetically heterogeneous with many implicated genes, however, only a few of these genes are reported in African populations.

Methods: This study used exome and Sanger sequencing to resolve the possible genetic cause of non-syndromic HI in a Ghanaian family.

Results: We identified a novel variant c.3041G > A: p.(Gly1014Glu) in GREB1L (DFNA80) in the index case. The GREB1L: p.(Gly1014Glu) variant had a CADD score of 26.5 and was absent from human genomic databases such as TopMed and gnomAD. In silico homology protein modeling approaches displayed major structural differences between the wildtype and mutant proteins. Additionally, the variant was predicted to probably affect the secondary protein structure that may impact its function. Publicly available expression data shows a higher expression of Greb1L in the inner ear of mice during development and a reduced expression in adulthood, underscoring its importance in the development of the inner ear structures.

Conclusion: This report on an African individual supports the association of GREB1L variant with non-syndromic HI and extended the evidence of the implication of GREB1L variants in HI in diverse populations.

Keywords: GREB1L; Ghana; Hearing impairment.

Fig. 1

Pedigree, hearing impairment phenotype, and Sanger sequence validation of GREB1L: c.3041G > A variant. A Pedigree and genotype of the affected child (III:8), her mother (II) and brother. Squares represent males and circles females. The individual with the filed symbol is affected and clear symbols represent individuals without hearing impairment. B Pure tone audiograms of affected and unaffected family members. C Chromatograms showing GREB1L: c.3041G > A genotypes. D GREB1L protein sequence alignment has shown conservation of the amino acid at position 1014

Fig. 2

In silico GREB1L protein analysis showing structural variations between the modelled wildtype and mutant proteins. A Cellular organization of GREB1L as predicted using PROTTER [28], an online bioinformatic tool. Homology modelling represented in B Superimposition of full-length wildtype and truncated mutant GREB1L structures. C Formation of helix at ¹⁴⁶⁹SSMLG¹⁴⁷³ in the mutant. D shortening of helix at ¹⁵⁵⁹KY¹⁵⁶⁰ and beta strand at ¹⁵⁴⁴LHLLVV¹⁵⁴⁹ in the mutant. E and F Extension of helices at ¹⁰⁹³DLSG¹⁰⁹⁶ and ⁹²³TT⁹²⁴ in the mutant. Yellow circles denote sites of different secondary structural changes of the mutant compared to the wildtype structures. Hydrogen-bond formation of G wildtype and H mutant residues with nearby residues. H-bond between K¹⁰¹⁰ and R¹⁰¹³ residues is lost in the mutant, and the H-bond lengths are shortened in the mutant compared to the wildtype