RT Journal Article
SR Electronic
T1 Otitis media susceptibility and shifts in the head and neck microbiome due to <em>SPINK5</em> variants
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 442
OP 452
DO 10.1136/jmedgenet-2020-106844
VO 58
IS 7
A1 Frank, Daniel N.
A1 Giese, Arnaud P. J.
A1 Hafren, Lena
A1 Bootpetch, Tori C.
A1 Yarza, Talitha Karisse L.
A1 Steritz, Matthew J.
A1 Pedro, Melquiadesa
A1 Labra, Patrick John
A1 Daly, Kathleen A.
A1 Tantoco, Ma. Leah C.
A1 Szeremeta, Wasyl
A1 Reyes-Quintos, Maria Rina T.
A1 Ahankoob, Niaz
A1 Llanes, Erasmo Gonzalo d.V.
A1 Pine, Harold S.
A1 Yousaf, Sairah
A1 Ir, Diana
A1 Einarsdottir, Elisabet
A1 de la Cruz, Rhodieleen Anne R.
A1 Lee, Nanette R.
A1 Nonato, Rachelle Marie A.
A1 Robertson, Charles E.
A1 Ong, Kimberly Mae C.
A1 Magno, Jose Pedrito M.
A1 Chiong, Alessandra Nadine E.
A1 Espiritu-Chiong, Ma. Carmina
A1 San Agustin, Maria Luz
A1 Cruz, Teresa Luisa G.
A1 Abes, Generoso T.
A1 Bamshad, Michael J.
A1 Cutiongco-de la Paz, Eva Maria
A1 Kere, Juha
A1 Nickerson, Deborah A.
A1 Mohlke, Karen L.
A1 Riazuddin, Saima
A1 Chan, Abner
A1 Mattila, Petri S.
A1 Leal, Suzanne M.
A1 Ryan, Allen F.
A1 Ahmed, Zubair M.
A1 Chonmaitree, Tasnee
A1 Sale, Michele M.
A1 Chiong, Charlotte M.
A1 Santos-Cortez, Regie Lyn P.
YR 2021
UL http://jmg.bmj.com/content/58/7/442.abstract
AB 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 &gt;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&gt;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.Data are available in a public, open access repository. Novel variants are cited in ClinVar with accession numbers SCV001338935-SCV001338943. Demultiplexed paired-end 16S rRNA sequence data were deposited in the NCBI Short Read Archive under accession number PRJNA439435. RNA-sequence data from cholesteatoma and mucosal samples from OM patients [40] are available in dbGaP:phs001941.v1.p1.