RT Journal Article SR Electronic T1 Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2020-106844 DO 10.1136/jmedgenet-2020-106844 A1 Daniel N. Frank A1 Arnaud P. J. Giese A1 Lena Hafren A1 Tori C. Bootpetch A1 Talitha Karisse L. Yarza A1 Matthew J. Steritz A1 Melquiadesa Pedro A1 Patrick John Labra A1 Kathleen A. Daly A1 Ma. Leah C. Tantoco A1 Wasyl Szeremeta A1 Maria Rina T. Reyes-Quintos A1 Niaz Ahankoob A1 Erasmo Gonzalo d.V. Llanes A1 Harold S. Pine A1 Sairah Yousaf A1 Diana Ir A1 Elisabet Einarsdottir A1 Rhodieleen Anne R. de la Cruz A1 Nanette R. Lee A1 Rachelle Marie A. Nonato A1 Charles E. Robertson A1 Kimberly Mae C. Ong A1 Jose Pedrito M. Magno A1 Alessandra Nadine E. Chiong A1 Ma. Carmina Espiritu-Chiong A1 Maria Luz San Agustin A1 Teresa Luisa G. Cruz A1 Generoso T. Abes A1 Michael J. Bamshad A1 Eva Maria Cutiongco-de la Paz A1 Juha Kere A1 Deborah A. Nickerson A1 Karen L. Mohlke A1 Saima Riazuddin A1 Abner Chan A1 Petri S. Mattila A1 Suzanne M. Leal A1 Allen F. Ryan A1 Zubair M. Ahmed A1 Tasnee Chonmaitree A1 Michele M. Sale A1 Charlotte M. Chiong A1 Regie Lyn P. Santos-Cortez YR 2020 UL http://jmg.bmj.com/content/early/2020/07/24/jmedgenet-2020-106844.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 >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.