Auditory Phenotype of a Novel Missense Variant in the CEACAM16 Gene in a Large Russian Family With Autosomal Dominant Nonsyndromic Hearing Loss

Abstract

Autosomal dominant hearing loss is represented by a large number of genetically determined forms. Over 50 genes associated with dominant nonsyndromic hearing impairments were described. Pathogenic variants in the CEACAM16 gene lead to the development of DFNA4B hearing loss. Currently, 8 pathogenic variants in this gene have been described. The objective of this study was to study the audiological and molecular genetic characteristics of a large family with CEACAM16-associated autosomal dominant nonsyndromic hearing loss. A detailed anamnesis was collected, and a comprehensive audiological examination was performed for 21 family members. Genetic testing was performed, including whole-genome sequencing for the proband's son and Sanger sequence analysis for the proband and for all available family members. In a large Russian family, including 5 generations, an autosomal dominant type of slowly progressing nonsyndromic late-onset hearing loss was observed. Eleven family members suffer from hearing impairment, which starts with tinnitus and threshold increase at high frequencies, since the age of 5-20 years. Hearing loss slowly progresses with age in each person and is similar to age-related hearing loss. We have detected the novel likely pathogenic variant с.419С>T (p.(Thr140Ile)) in exon 3 of the CEACAM16 gene, which segregates with late-onset nonsyndromic hearing loss in this family. The clinical data obtained in the examined family correspond with the phenotype in previously described cases. In general, the study widened the mutation spectrum of the gene, allowing to carry out medical genetic counseling and to answer the questions about the hearing impairment prognosis for future generations.

Figure 1.

Family tree of a large Russian family with late-onset ADSNHL carrying a missense mutation in the CEACAM16 gene. Squares and circles represent females and males; shaded: family members with hearing impairment; white: healthy. Subjects younger than the onset age with an intangible hearing status are marked with minute shading and a question mark, and deceased family members are marked with a slash. The arrow points at the proband (IV:9). Twenty-one family members included in the linkage analysis are marked with an asterisk.

Figure 2.

Air conduction audiograms of the core family (proband, her mother, siblings, and children) performed at different ages.

Figure 3.

Genetic testing of the family with a variant in the CEACAM16 gene. Sanger traces demonstrating the c.419C>T heterozygous missense CEACAM16 mutation in the proband and the proband’s son.