CEACAM16 – Autosomal Dominant Nonsyndromic Hearing Loss (DFNA4B)

CEACAM16 encodes a secreted glycoprotein of the tectorial membrane and has been implicated in autosomal dominant nonsyndromic hearing loss (DFNA4B) (MONDO:0019587). Pathogenic variants disrupt cochlear tectorial membrane integrity, leading to postlingual progressive sensorineural hearing impairment (HP:0000365) often accompanied by tinnitus (HP:0000360).

Initial reports described two multigenerational families with segregating missense mutations in the immunoglobulin constant domain A. A de novo heterozygous c.1094T>G (p.Leu365Arg) variant was identified in a parent–child trio with no family history, confirmed by Sanger sequencing and STR analysis, and matches the DFNA4B phenotype ([PMID:26648831]).

Subsequent studies expanded the mutational spectrum. In a five‐generation Russian pedigree, a novel c.419C>T (p.Thr140Ile) substitution segregated with hearing loss in 11 affected individuals ([PMID:39157884]). In an independent Chinese family, a heterozygous c.505G>C (p.Gly169Arg) variant co-segregated fully with late-onset progressive hearing loss in all tested relatives of SY-026 ([PMID:25589040]).

Loss‐of‐function and splice‐altering alleles have also been described in recessive cases. A homozygous c.859del (p.Gln287fs) frameshift was reported in consanguineous families with postlingual AR hearing loss ([PMID:30514912]). Minigene assays demonstrated that c.37G>T and c.662-1G>C abolish canonical splicing, leading to exon skipping and frameshifts ([PMID:29703829]).

Functional assays in transfected HEK293T cells show that missense variants reduce secretion efficiency and alter intracellular retention, while overexpressed p.Arg255Gly yields increased extracellular secretion with potential dominant‐negative effects ([PMID:25589040]; [PMID:35292975]). These studies support a mechanism of disrupted tectorial membrane homeostasis.

Collectively, four independent AD families with >15 affected individuals, de novo occurrence, segregation across generations, and concordant functional data establish a Strong clinical validity for CEACAM16 in DFNA4B. Functional evidence is rated Moderate based on secretion and splicing assays. CEACAM16 testing enables definitive molecular diagnosis and informs prognosis and genetic counseling.

References

• Molecular syndromology • 2015 • A Novel de novo Mutation in CEACAM16 Associated with Postlingual Hearing Impairment. PMID:26648831
• The journal of international advanced otology • 2024 • Auditory Phenotype of a Novel Missense Variant in the CEACAM16 Gene in a Large Russian Family With Autosomal Dominant Nonsyndromic Hearing Loss. PMID:39157884
• Journal of human genetics • 2015 • Exome sequencing identifies a novel CEACAM16 mutation associated with autosomal dominant nonsyndromic hearing loss DFNA4B in a Chinese family. PMID:25589040
• Journal of medical genetics • 2018 • Old gene, new phenotype: splice-altering variants in CEACAM16 cause recessive non-syndromic hearing impairment. PMID:29703829
• Journal of human genetics • 2019 • Further evidence for loss-of-function mutations in the CEACAM16 gene causing nonsyndromic autosomal recessive hearing loss in humans. PMID:30514912
• Annals of human genetics • 2022 • A novel missense variant in CEACAM16 gene causes autosomal dominant nonsyndromic hearing loss. PMID:35292975

Evidence Based Scoring (AI generated)