Alternative titles; symbols
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12p13.31 | {Otitis media, susceptibility to} | 166760 | Autosomal dominant | 3 | A2ML1 | 610627 |
A number sign (#) is used with this entry because of evidence that susceptibility to otitis media may be conferred by variation in the A2ML1 gene (610627) on chromosome 12p13.
A genetic contribution to susceptibility to otitis media is suggested by racial variations; the frequency is unusually high in American Indians and Australian aborigines and comparatively low in blacks. Family studies have suggested familial aggregation for otitis media, mastoid size, and cholesteatoma. Todd (1987) studied otitis media in Apache Indians in Arizona. The findings suggested familial predisposition.
Casselbrant et al. (1999) estimated the heritability of otitis media by means of a twin and triplet study. They recruited 168 healthy same-sex twin and 7 triplet sets within the first 2 months of life. They compared the time with middle ear effusion, the number of episodes of middle ear effusion, and the episodes of acute otitis media according to zygosity status. At the end of a 2-year period, the estimate of heritability of time with middle ear effusion was 0.73 (P less than 0.001). The estimates of discordance for 3 or more episodes of middle ear effusion were 0.04 for monozygotic twins and 0.37 for dizygotic twins (P = 0.01). The estimate of discordance of an episode of acute otitis media in monozygotic twins was 0.04 compared with 0.49 in dizygotic twins (P = 0.005).
Ehrlich and Post (1999) editorialized the demonstration by Casselbrant et al. (1999) that otitis media in children has a strong heritable component, stating that, for primary care clinicians, the lesson is that once an otitis media-prone child is identified, closer observation of sibs is indicated.
There is evidence that chronic/recurrent otitis media (COME/ROM) clusters in families and exhibits substantial heritability. Daly et al. (2004) studied probands who had tympanostomy tube surgery for COME/ROM and their families. Of these families, 121 had at least 2 individuals who had received the diagnosis of COME/ROM, of whom 238 affected and informative relative pairs were used for analyses. Single-point nonparametric linkage analysis provided evidence of linkage to marker D10S212 on 10q26.3 (lod = 3.78, p = 0.00003) and to marker D19S254 on 19q13.42-q13.43 (lod = 2.61, p = 0.00053). Analyses conditional on support for linkage at chromosomes 10q and 19q resulted in a significant increase in lod score support on chromosome 3p25.3 (between markers D3S4545 and D3S1259). Daly et al. (2004) concluded that risk of COME/ROM is determined by interactions between genes that reside in several candidate regions of the genome and are probably modulated by other environmental risk factors.
In 134 individuals from an intermarried, indigenous Filipino population with high frequency of otitis media, Santos-Cortez et al. (2015) identified an 8-bp duplication in the A2ML1 gene (c.2478_2485dupGGCTAAAT; 610627.0004), resulting in a frameshift and premature termination (Ser829TrpfsTer9). The variant was predicted to result in nonsense-mediated mRNA decay and a loss of thiol-ester and receptor binding domains. The variant was found by exome sequencing and confirmed by Sanger sequencing. Assuming 95% penetrance and a 5% phenocopy rate, the lod score for the variant was 7.5. Direct sequencing of the A2ML1 gene identified the same intragenic duplication in 3 of 123 otitis-prone children from a different cohort. Two children, of European American and Hispanic origin, were homozygous for the duplication, whereas the third child of European American descent was heterozygous for the variant. The variant was absent in 118 children who were not prone to otitis media. Haplotype analysis indicated a founder effect for this variant. Seven additional heterozygous variants in the A2ML1 gene, including 3 nonsense and 4 missense, were identified in 7 patients of Hispanic or European American descent with chronic or recurrent otitis media. Five of these variants were not found in the ExAC database; familial segregation information was not available. Functional studies of any of the variants and studies of patient cells were not performed. Santos-Cortez et al. (2015) demonstrated that the A2ml1 gene is expressed in murine epithelial cells in the middle ear, and postulated that it may have a protective function within the middle ear.
In a follow-up study analyzing genetic and environmental risk factors for otitis media in the Filipino population, Santos-Cortez et al. (2016) concluded that there was no association between otitis media and gender, body mass index, breastfeeding, tobacco exposure, or deep swimming. Multivariate analyses indicated that the A2ML1 genotype was the strongest predictor of otitis media, with an odds ratio of 3.7 (p = 0.005). In this group, otitis media was observed within the first year of life and chronic otitis media persisted to adulthood, particularly in carriers of the A2ML1 variant. There was a 48.7% prevalence of otitis media in this population.
Depreux et al. (2008) found that Eya4 (603550)-null mice had severe hearing deficits and developed otitis media with effusion. All 50 mutant mice showed hypervascularity of the tympanic membrane, marked retraction of the tympanic membrane, and middle ear effusions consistent with otitis media. Fifty control mice showed no such abnormalities. Anatomic studies of mutant mice showed an abnormal middle ear cavity and dysmorphology of the eustachian tube. The authors postulated that susceptibility to human otitis media may involve genetic variation in genes such as EYA4 that regulate middle ear and eustachian tube anatomy.
Casselbrant, M. L., Mandel, E. M., Fall, P. A., Rockette, H. E., Kurs-Lasky, M., Bluestone, C. D., Ferrell, R. E. The heritability of otitis media: a twin and triplet study. JAMA 282: 2125-2130, 1999. [PubMed: 10591333] [Full Text: https://doi.org/10.1001/jama.282.22.2125]
Daly, K. A., Brown, W. M., Segade, F., Bowden, D. W., Keats, B. J., Lindgren, B. R., Levine, S. C., Rich, S. S. Chronic and recurrent otitis media: a genome scan for susceptibility loci. Am. J. Hum. Genet. 75: 988-997, 2004. Note: Erratum: Am. J. Hum. Genet. 76: 196 only, 2005. [PubMed: 15514890] [Full Text: https://doi.org/10.1086/426061]
Depreux, F. F. S., Darrow, K., Conner, D. A., Eavey, R. D., Liberman, M. C., Seidman, C. E., Seidman, J. G. Eya4-deficient mice are a model for heritable otitis media. J. Clin. Invest. 118: 651-658, 2008. [PubMed: 18219393] [Full Text: https://doi.org/10.1172/JCI32899]
Ehrlich, G. D., Post, J. C. Susceptibility to otitis media: strong evidence that genetics plays a role. (Editorial) JAMA 282: 2167-2169, 1999. [PubMed: 10591340] [Full Text: https://doi.org/10.1001/jama.282.22.2167]
Santos-Cortez, R. L. P., Chiong, C. M., Reyes-Quintos, M. R. T., Tantoco, M. L. C., Wang, X., Acharya, A., Abbe, I., Giese, A. P., Smith, J. D., Allen, E. K., Li, B., Cutiongco-de la Paz, E. M., and 18 others. Rare A2ML1 variants confer susceptibility to otitis media. Nature Genet. 47: 917-920, 2015. [PubMed: 26121085] [Full Text: https://doi.org/10.1038/ng.3347]
Santos-Cortez, R. L. P., Reyes-Quintos, M. R. T., Tantoco, M. L. C., Abbe, I., Llanes, E. G. D. V., Ajami, N. J., Hutchinson, D. S., Petrosino, J. F., Padilla, C. D., Villarta, R. L., Jr., Gloria-Cruz, T. L., Chan, A. L., Cutiongco-de la Paz, E. M., Chiong, C. M., Leal, S. M., Abes, G. T. Genetic and environmental determinants of otitis media in an indigenous Filipino population. Otolaryng. Head Neck Surg. 155: 856-862, 2016. [PubMed: 27484237] [Full Text: https://doi.org/10.1177/0194599816661703]
Todd, N. W. Familial predisposition for otitis media in Apache Indians at Canyon Day, Arizona. Genet. Epidemiol. 4: 25-31, 1987. [PubMed: 3569876] [Full Text: https://doi.org/10.1002/gepi.1370040104]