A novel variant in DMXL2 gene is associated with autosomal dominant non-syndromic hearing impairment (DFNA71) in a Cameroonian family

Abstract

Approximately half of congenital hearing impairment cases are inherited, with non-syndromic hearing impairment (NSHI) being the most frequent clinical entity of genetic hearing impairment cases. A family from Cameroon with NSHI was investigated by performing exome sequencing using DNA samples obtained from three family members, followed by direct Sanger sequencing in additional family members and controls participants. We identified an autosomal dominantly inherited novel missense variant [NM_001174116.2:c.918G>T; p.(Q306H)] in DMXL2 gene (MIM:612186) that co-segregates with mild to profound non-syndromic sensorineural hearing impairment . The p.(Q306H) variant which substitutes a highly conserved glutamine residue is predicted deleterious by various bioinformatics tools and is absent from several genome databases. This variant was also neither found in 121 apparently healthy controls without a family history of hearing impairment , nor 112 sporadic NSHI cases from Cameroon. There is one previous report of a large Han Chinese NSHI family that segregates a missense variant in DMXL2. The present study provides additional evidence that DMXL2 is involved in hearing impairment etiology, and we suggest DMXL2 should be considered in diagnostic hearing impairment panels.

Keywords: Africa; DMXL2; Non-syndromic hearing impairment; autosomal dominant inheritance.

Figure 1.

Pedigree, audiometry results, and sequencing chromatograms of family 23. (a) The family tree and co-segregation of the DMXL2 variant NM_015263.5:c.918G>T are compatible with AD mode of inheritance of the HI within the family. The proband is designated by the black arrow. (b) Pure tone audiometry (air conduction) of the three affected individuals, showing a bilateral profound hearing loss for the mother (I.2), a bilateral mild HI for child II.2, and bilateral profound HI for child II.4. (c) Sequencing chromatograms displaying the wild type and variant alleles. The red arrow indicates the nucleotide where the variant occurs. Het: heterozygous for the alternate allele; Wt: homozygous for the wild type; yo: years old.

Figure 2.

Conservation of the mutational position DMXL2:p.(Q306H) (designated by the red arrow) across species.

Figure 3.

Model of the 3D structures of wild-type DMXL2 and its Q306H mutant. (a) The overall structure of DMXL2 (b) Close-up view of the interactions at position 306 of wild and Q306H (c). The wild and mutant are represented by green and red colors, respectively. The superposed structure of wild and mutant type (d) shows the shortening of the β-strand in the mutant protein as indicated by an arrow in the close-up view (e).