Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants.

BACKGROUND: Otitis media (OM) susceptibility has significant heritability; however, the role of rare variants in OM is mostly unknown. Our goal is to identify novel rare variants that confer OM susceptibility. METHODS: We performed exome and Sanger sequencing of >1000 DNA samples from 551 multiethnic families with OM and unrelated individuals, RNA-sequencing and microbiome sequencing and analyses of swabs from the outer ear, middle ear, nasopharynx and oral cavity. We also examined protein localisation and gene expression in infected and healthy middle ear tissues. RESULTS: A large, intermarried pedigree that includes 81 OM-affected and 53 unaffected individuals cosegregates two known rare A2ML1 variants, a common FUT2 variant and a rare, novel pathogenic variant c.1682A>G (p.Glu561Gly) within SPINK5 (LOD=4.09). Carriage of the SPINK5 missense variant resulted in increased relative abundance of Microbacteriaceae in the middle ear, along with occurrence of Microbacteriaceae in the outer ear and oral cavity but not the nasopharynx. Eight additional novel SPINK5 variants were identified in 12 families and individuals with OM. A role for SPINK5 in OM susceptibility is further supported by lower RNA counts in variant carriers, strong SPINK5 localisation in outer ear skin, faint localisation to middle ear mucosa and eardrum and increased SPINK5 expression in human cholesteatoma. CONCLUSION: SPINK5 variants confer susceptibility to non-syndromic OM. These variants potentially contribute to middle ear pathology through breakdown of mucosal and epithelial barriers, immunodeficiency such as poor vaccination response, alteration of head and neck microbiota and facilitation of entry of opportunistic pathogens into the middle ear.

Auditory steady state response (ASSR) frequency-specific thresholds with absent auditory brainstem response (click-ABR) test results among Filipino children

@#OBJECTIVE: Determine the frequency-specific thresholds of auditory steady state response (ASSR) of Filipino children with absent auditory brainstem response (click-ABR) results.METHODS: This is a cross-sectional study analyzing the frequency-specific thresholds of auditory steady state response (ASSR) of Filipino children with absent auditory brainstem response (click-ABR) results. The study population comprised of 99 pediatric patients referred for hearing assessment using electrophysiologic techniques at the Ear Unit of the Philippine General Hospital. The subjects underwent hearing threshold evaluation using both evoked-potential techniques (click ABR and ASSR) within a one-month period from January 2009 to March 2014. The ASSR results of patients with absent click-ABR were collected and analyzed.RESULTS: There were 99 patients who underwent both ABR and ASSR. Of the 65 patients with absent ABR thresholds results, 13 patients had unilateral absent ABR while 52 had bilateral absent ABR results. The data of hearing tests from the combined 117 ears with absent ABR hearing tests were collected. The proportion of children with ASSR thresholds with absent ABR per frequency were -500 Hz- 45/117 (38.5%); -1000 Hz- 76/117 (64.0%); -2000 Hz- 63/117 (53.8%); and -4000 Hz- 41/117 (35.0%). The proportion of children with ASSR thresholds with absent ABR per number of frequencies were: -4 frequencies- 19/117 (16.2%); -3 frequencies- 32/117 (27.4%); -2 frequencies- 22/117 (18.8%); and -1 frequency- 44/117 (37.6%)CONCLUSION: In the absence of click- ABR response, ASSR may provide information about the levels of severe to profound hearing loss among children. The criteria of selection of candidates for intervention (hearing aids or cochlear implantation) should include results from hearing evaluation not only from behavioral and ABR thresholds but also from ASSR thresholds. This may ensure that exclusion of some children with severe and profound hearing loss who may benefit from the intervention will be minimized.