At the University of Maryland Medical Center (UMMC), Saima Riazuddin, PhD, MPH, MBA, Professor of Otorhinolaryngology and Biochemistry, leads a lab dedicated to inner ear and brain research. Riazuddin and her team utilize human genetics, mouse, and zebrafish model systems to identify genes responsible for various inherited disorders. Her scientific accomplishments have earned several national and international awards, including a Medal of Honor by the President of Pakistan.

In a recent multi-institutional study, Riazuddin, along with colleagues from UMMC and other institutions, published an original research paper, “Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants,” in the Journal of Medical Genetics.1

Otitis media (OM) is a common childhood disease characterized by middle ear inflammation, affecting ~50% of children < 1-year-old. Around 17% of these patients require surgery for recurrent acute OM or chronic OM with a fivefold increased risk for OM surgery among first-degree relatives.1

OM susceptibility has significant heritability; however, the role of rare variants in OM is primarily unknown. Previously, the multi-institutional study team identified two rare A2ML1 (MIM 610627) variants (one duplication and one splice) and a common FUT2 (MIM 182100) variant in an intermarried, indigenous Filipino population (n~250) with a ~50% prevalence of non-syndromic OM.

The goal of the recent study was to identify rare novel variants that confer OM susceptibility. The multi-institutional research team 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. They also examined protein localization and gene expression in infected and healthy middle ear tissues.1

In the large, intermarried pedigree that included 81 OM-affected and 53 unaffected individuals, 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) were identified.1

Carriage of the SPINK5 missense variant resulted in the increased relative abundance of Microbacteriaceae in the middle ear and the 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.1

A role for SPINK5 in OM susceptibility is further supported by lower RNA counts in variant carriers, strong SPINK5 localization in outer ear skin, faint localization to middle ear mucosa and eardrum, and increased SPINK5 expression in human cholesteatoma.1

The findings demonstrated that SPINK5 variants confer susceptibility to non-syndromic OM in multiethnic families and individuals. The authors conclude that these variants potentially contribute to middle ear pathology through the breakdown of mucosal and epithelial barriers, immunodeficiencies such as poor vaccination response, alteration of head and neck microbiota, and facilitation of entry of opportunistic pathogens into the middle ear. 1

Learn more about the Department of Otorhinolaryngology- Head & Neck Surgery at University of Maryland Medical Center.

  1. Frank DN, Giese APJ, Hafren L, Bootpetch TC, Yarza TKL, Steritz MJ, Pedro M, Labra PJ, Daly KA, Tantoco MLC, Szeremeta W, Reyes-Quintos MRT, Ahankoob N, Llanes EGDV, Pine HS, Yousaf S, Ir D, Einarsdottir E, de la Cruz RAR, Lee NR, Nonato RMA, Robertson CE, Ong KMC, Magno JPM, Chiong ANE, Espiritu-Chiong MC, San Agustin ML, Cruz TLG, Abes GT, Bamshad MJ, Cutiongco-de la Paz EM, Kere J, Nickerson DA, Mohlke KL, Riazuddin S, Chan A, Mattila PS, Leal SM, Ryan AF, Ahmed ZM, Chonmaitree T, Sale MM, Chiong CM, Santos-Cortez RLP. Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants. J Med Genet. 2020 Jul 24:jmedgenet-2020-106844. doi: 10.1136/jmedgenet-2020-106844. Epub ahead of print. PMID: 32709676; PMCID: PMC8218788.