Santos-Cortez Regie Lyn P, Elling Christina L, Gomez Helen Z, Einarsdottir Elisabet, Kere Juha, Mattila Petri S, Hafrén Lena, Ryan Allen F
Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave., MS:8606, Aurora, CO, 80045, USA.
Science for Life Laboratory, Department of Gene Technology, KTH-Royal Institute of Technology, 171 21, Solna, Sweden.
J Mol Med (Berl). 2025 May;103(5):559-570. doi: 10.1007/s00109-025-02537-w. Epub 2025 Apr 4.
Otitis media is a highly frequent diagnosis in children that causes significant morbidity but remains understudied as a genetic trait despite significant heritability in families. To identify rare or low-frequency variants within genes that confer susceptibility to otitis media, exome sequence data of 287 individuals from 243 families were analyzed. Identified variants were tested for co-segregation with otitis media in family members. Genome sequence data from a case-control cohort was imputed and analyzed for association of specific genes with otitis media. Single-cell RNA-sequence data of identified genes were noted in acutely infected mouse middle ears. Thirty-three variants within 24 genes co-segregated with otitis media in 28 families, of which 18 variants were considered pathogenic or likely pathogenic. An additional 81 variants in 21 of the same genes were identified in 83 unrelated probands with otitis media. Of the 24 genes, 12 were associated with otitis media in mouse models, while 15 genes were replicated from previous human studies. A common variant EYA4 c.829G > A was associated with OM in the case-control cohort. Using network analysis, 22 of the 24 genes were connected in a subnetwork enriched in various signaling pathways, Th1/Th2/Th17 cell differentiation, and viral infections. Majority (87.5%) of the identified genes were expressed in mouse middle ear cells, with differential expression after acute infection. The identification of novel genes and variants for susceptibility to otitis media will be useful in future risk screening and clinical management in children that require a more personalized approach due to poor response to standard treatments. KEY MESSAGES: Thirty-three variants in 24 genes were identified in 28 families with otitis media. Eighteen of these variants within 10 genes were considered (likely) pathogenic. A common variant EYA4 c.829G > A was associated with OM in a case-control cohort. The novel genes were differentially expressed in mouse middle ear post-infection. Genetic screening could identify children for targeted treatment for otitis media.
中耳炎是儿童中一种非常常见的诊断疾病，它会导致严重的发病率，但尽管在家族中有显著的遗传度，作为一种遗传特征仍未得到充分研究。为了识别导致中耳炎易感性的基因中的罕见或低频变异，分析了来自243个家庭的287名个体的外显子组序列数据。对鉴定出的变异进行了家庭成员中耳炎共分离测试。对病例对照队列的基因组序列数据进行了推算，并分析了特定基因与中耳炎的关联。在急性感染的小鼠中耳中记录了已鉴定基因的单细胞RNA序列数据。28个家庭中有24个基因的33个变异与中耳炎共分离，其中18个变异被认为是致病的或可能致病的。在83名患有中耳炎的无关先证者中，在相同的21个基因中又鉴定出另外81个变异。在这24个基因中，有12个在小鼠模型中与中耳炎相关，而有15个基因是从先前的人类研究中复制而来的。一个常见变异EYA4 c.829G＞A在病例对照队列中与中耳炎相关。使用网络分析，24个基因中的22个在一个富含各种信号通路、Th1/Th2/Th17细胞分化和病毒感染的子网中相互连接。大多数（87.5%）已鉴定的基因在小鼠中耳细胞中表达，急性感染后表达有差异。鉴定中耳炎易感性的新基因和变异将有助于未来对儿童进行风险筛查和临床管理，由于对标准治疗反应不佳，这些儿童需要更个性化的方法。关键信息：在28个患有中耳炎的家庭中鉴定出24个基因的33个变异。其中10个基因中的18个变异被认为是（可能）致病的。一个常见变异EYA4 c.829G＞A在病例对照队列中与中耳炎相关。这些新基因在感染后的小鼠中耳中表达有差异。基因筛查可以识别出适合针对性治疗中耳炎的儿童。
