Old gene, new phenotype: splice-altering variants in CEACAM16 cause recessive non-syndromic hearing impairment.

BACKGROUND: Hearing loss is a genetically and phenotypically heterogeneous disorder. OBJECTIVES: The purpose of this study was to determine the genetic cause underlying the postlingual progressive hearing loss in two Iranian families. METHODS: We used OtoSCOPE, a next-generation sequencing platform targeting >150 genes causally linked to deafness, to screen two deaf probands. Data analysis was completed using a custom bioinformatics pipeline, and variants were functionally assessed using minigene splicing assays. RESULTS: We identified two homozygous splice-altering variants (c.37G>T and c.662-1G>C) in the CEACAM16 gene, segregating with the deafness in each family. The minigene splicing results revealed the c.37G>T results in complete skipping of exon 2 and loss of the AUG start site. The c.662-1G>C activates a cryptic splice site inside exon 5 resulting in a shift in the mRNA reading frame. CONCLUSIONS: These results suggest that loss-of-function mutations in CEACAM16 result in postlingual progressive hearing impairment and further support the role of CEACAM16 in auditory function.