Rare A2ML1 variants confer susceptibility to otitis media

Santos‐Cortez, Regie Lyn P.; Chiong, Charlotte M.; Reyes-Quintos, Ma. Rina T.; Tantoco, Ma. Leah C.; Wang, Xin; Acharya, Anushree; Abbe, Izoduwa; Giese, Arnaud P. J.; Smith, Joshua D.; Allen, E. Kaitlynn; Li, Biao; Paz, Eva Maria Cutiongco‐de la; Garcia, Marieflor Cristy M.; Llanes, Erasmo Gonzalo D.V.; Labra, Patrick John; Gloria-Cruz, Teresa Luisa I; Chan, Abner L.; Wang, Gao T.; Daly, Kathleen A.; Shendure, Jay; Bamshad, Michael J.; Nickerson, Deborah A.; Patel, Janak A.; Riazuddin, Saima; Sale, Michèle M.; Chonmaitree, Tasnee; Ahmed, Zubair M.; Abes, Generoso T.

doi:10.1038/ng.3347

Cited by 41 publications

(65 citation statements)

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“…A2ML1 codes for alpha-2-macroglobulin-like 1 and has been discussed in the context of Noonan syndrome, but all variants were classified as variants of unknown significance because their contribution to Noonan syndrome could not be confirmed 5. Copy number variants and heterozygous rare variants in A2ML1 have also been described to be associated with otitis media in children 6. The prevalence of loss-of-function variants for A2ML1 is relatively high in the ExAC database.…”

Section: Resultsmentioning

confidence: 99%

Mutations in plasmalemma vesicle-associated protein cause severe syndromic protein-losing enteropathy

et al. 2018

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Section: Resultsmentioning

confidence: 99%

Mutations in plasmalemma vesicle-associated protein cause severe syndromic protein-losing enteropathy

et al. 2018

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“…DNA samples were Sanger-sequenced for the A2ML1 duplication variant [6]. From indigenous Filipinos with perforated eardrum(s) due to chronic otitis media, outer ear swabs were collected prior to middle ear swabs, using sterile short polyester-tipped Pur-Wrap swabs (Puritan Medical, Guilford, ME, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Recently we identified rare variants in the A2ML1 gene, which encodes alpha-2-macroglobulin-like 1 protein, as a cause of otitis media susceptibility [6]. A rare A2ML1 duplication variant c.2478_2485dupGGCTAAAT (p.(Ser829Trpfs*9)) confers susceptibility to otitis media in three European- or Hispanic-American children in Texas, USA and an indigenous Filipino population.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally the three US children who also carry the A2ML1 duplication variant had early-onset recurrent otitis media that required tympanostomy tube insertion within the first six months of age. The duplication variant occurred within a short haplotype that was common among the indigenous Filipinos and the US children, suggesting a founder variant that is estimated to be 1 800 years old and that may have occurred within the Filipino and US populations through Spanish colonization [6]. …”

Section: Introductionmentioning

confidence: 99%

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Middle ear microbiome differences in indigenous Filipinos with chronic otitis media due to a duplication in the A2ML1 gene

et al. 2016

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BackgroundPreviously rare A2ML1 variants were identified to confer otitis media susceptibility in an indigenous Filipino community and in otitis-prone US children. The goal of this study is to describe differences in the middle ear microbiome between carriers and non-carriers of an A2ML1 duplication variant that increases risk for chronic otitis media among indigenous Filipinos with poor health care access.MethodsEar swabs were obtained from 16 indigenous Filipino individuals with chronic otitis media, of whom 11 carry the A2ML1 duplication variant. Ear swabs were submitted for 16S rRNA gene sequencing.ResultsGenotype-based differences in microbial richness, structure, and composition were identified, but were not statistically significant. Taxonomic analysis revealed that the relative abundance of the phyla Fusobacteria and Bacteroidetes, and genus Fusobacterium were nominally increased in carriers compared to non-carriers, but were non-significant after correction for multiple testing. We also detected rare bacteria including Oligella that was reported only once in the middle ear.ConclusionsThese findings suggest that A2ML1-related otitis media susceptibility may be mediated by changes in the middle ear microbiome. Knowledge of middle ear microbial profiles according to genetic background can be potentially useful for therapeutic and prophylactic interventions for otitis media and can guide public health interventions towards decreasing otitis media prevalence within the indigenous Filipino community.Electronic supplementary materialThe online version of this article (doi:10.1186/s40249-016-0189-7) contains supplementary material, which is available to authorized users.

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“…Thanks to next generation sequencing techniques, we are beginning to accumulate a large catalog of low-frequency and rare variants (1000Genomes Project Consortium 2015UK10K Consortium 2015; Genome of the Netherlands Consortium, 2014), a few of which have already been implicated in complex traits (Cohen et al 2005;Shuldiner et al 2009;Cruchaga et al 2014;Flannick et al 2014;Hoffman et al 2014;Lange et al 2014;Santos-Cortez et al 2015;Krumm et al 2015;Surakka et al 2015). However, current study designs are not optimal for detecting association with rare variants.…”

Section: Introductionmentioning

confidence: 99%

Finding Rare, Disease-Associated Variants in Isolated Groups: Potential Advantages of Mennonite Populations

Lopes¹,

Hou²,

Boldt³

et al. 2016

Human Biology

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Large-scale genotyping and next generation sequencing techniques have allowed great advances in the field of molecular genetics. Numerous common variants of low impact have been associated with many complex human traits and diseases, such as bipolar disorder and schizophrenia. Although they may exert a greater impact on risk, few rare disease variants have been found, owing to the greatly increased sample sizes that are typically necessary to demonstrate association with rarer variants. One alternative strategy is to study isolated populations, where historical bottlenecks reduce genetic diversity and some otherwise rare variants may drift to higher frequencies. Here we describe the Mennonite population settlements, considering their history of multiple bottlenecks followed by demographic expansion and a currently widespread geographical distribution. We argue that Mennonite populations are valuable partners for studies seeking to find genetic variants that exert a high impact on risk for a variety of common disorders, including mental illnesses.

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Rare A2ML1 variants confer susceptibility to otitis media

Cited by 41 publications

References 23 publications

Mutations in plasmalemma vesicle-associated protein cause severe syndromic protein-losing enteropathy

Mutations in plasmalemma vesicle-associated protein cause severe syndromic protein-losing enteropathy

Middle ear microbiome differences in indigenous Filipinos with chronic otitis media due to a duplication in the A2ML1 gene

Finding Rare, Disease-Associated Variants in Isolated Groups: Potential Advantages of Mennonite Populations

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