A Novel de novo Mutation in CEACAM16 Associated with Postlingual Hearing Impairment

Abstract

Mutations in CEACAM16 cause autosomal dominant nonsyndromic hearing loss (DFNA4B). So far, 2 families have been reported with segregating missense mutations, both in the immunoglobulin constant domain A of the CEACAM16 protein. In this study, we used the TruSight One panel to investigate a parent-child trio without familial history of hearing loss and one affected child. When filtering for recessive inheritance and de novo events, we discovered a de novo CEACAM16 mutation (c.1094T>G, p.Leu365Arg) as the sole likely pathogenic variant. The de novo mutation was confirmed by Sanger sequencing and STR analysis. The proband's hearing loss closely matches the described onset and severity for DFNA4B. We present the third CEACAM16 variant and the first de novo mutation in CEACAM16. This de novo mutation is robustly described as a pathogenic mutation according to in silico mutation prediction tools and affects a highly conserved amino acid in the most strongly conserved CEACAM16 N2 domain. Our strategy of screening family trios enhances de novo mutation discovery and the exclusion of other variants of potential interest through pedigree filtering.

Keywords: Autosomal dominant nonsyndromic hearing loss; CEACAM16; DFNA4B; De novo mutation; Next-generation sequencing; Parent-child trios.

Fig. 1

Schematic overview of CEACAM16 and mutational analysis. aCEACAM16 has 7 exons, including one noncoding exon 1. The known mutations are in the fourth exon (pink), whereas the novel mutation of the index is in exon 6 (turquois). b The amino acid sequence per exon is represented within each dashed boundary. The red amino acid represents overlapping amino acids between adjacent exons. Changes of the single amino acids by mutations are marked in pink for known mutations and turquois for our investigated mutation. c The amino acid sequence corresponding to each protein domain is demarcated by solid lines for the N1 domain (green), A domain (blue), B domain (purple) and N2 domain (red). The position of each of the 3 CEACAM16 variants is marked in each of the corresponding domains. CEACAM16 domain and exon boundaries were prepared using Ensembl release 75.

Fig. 2

Familial pedigree, Sanger sequence confirmation and audiogram profile in the investigated index. a Pedigree of the investigated index. Parents and an older sibling are healthy with normal hearing. There is no family history of hearing loss. b Validation by Sanger sequencing. Both parents and the sibling show the WT sequence in the c.1094 position (left). The heterozygous c.1094T>G mutation was confirmed in the index (right). c The child has a bilateral hearing loss that moderately affects all frequencies except 0.125 kHz.