A Contemporary Review of AudioGene audioprofiling: A machine‐based candidate gene prediction tool for autosomal dominant nonsyndromic hearing loss

Hildebrand, Michael S.; DeLuca, Adam P.; Taylor, Kyle R.; Hoskinson, David P.; Hur, In Ae; Tack, Dylan; McMordie, Sarah J.; Huygen, P.L.M.; Casavant, Thomas L.; Smith, Richard J.H.

doi:10.1002/lary.20664

Cited by 39 publications

(42 citation statements)

References 7 publications

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“…All probands recruited to the study were screened for population-specific deafness alleles (Supplementary Table 1; Abdelfatah et al 2013a, b; Ahmed et al 2004; Doucette et al 2009; Young et al 2001). To identify other candidate genes to screen, audiograms were submitted to Audiogene (Hildebrand et al 2009) for computerized comparison with known average audiograms of 16 autosomal dominant loci (under the assumption that hearing loss was segregating as an autosomal dominant trait in these NL families). Bidirectional Sanger sequencing (ABI PRISM 3500XL DNA Analyzer; Applied Biosystems, Foster City, CA, USA) with standard PCR assay using Primer3 (Untergasser et al 2012) was used to screen candidate mutations and genes (Merner et al 2008).…”

Section: Methodsmentioning

confidence: 99%

A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect

et al. 2016

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Genetic isolates provide unprecedented opportunities to identify pathogenic mutations and explore the full natural history of clinically heterogeneous phenotypes such as hearing loss. We noticed a unique audioprofile, characterized by prelingual and rapid deterioration of hearing thresholds at frequencies >0.5 kHz in several adults from unrelated families from the island population of Newfoundland. Targeted serial Sanger sequencing of probands for deafness alleles (n = 23) that we previously identified in this founder population was negative. Whole exome sequencing in four members of the largest family (R2010) identified a CLDN14 (DFNB29) variant [c.488C>T; p. (Ala163Val)], likely pathogenic, sensorineural hearing loss, autosomal recessive. Although not associated with deafness or disease, CLDN14 p.(Ala163Val) has been previously reported as a variant of uncertain significance (VUS). Targeted sequencing of 169 deafness probands identified one homozygote and one heterozygous carrier. Genealogical studies, cascade sequencing and haplotype analysis across four unrelated families showed all subjects with the unique audioprofile (n = 12) were also homozygous for p.(Ala163Val) and shared a 1.4 Mb DFNB29-associated haplotype on chromosome 21. Most significantly, sequencing 175 population controls revealed 1% of the population are heterozygous for CLDN14 p.(Ala163Val), consistent with a major founder effect in Newfoundland. The youngest CLDN14 [c.488C>T; p.(Ala163Val)] homozygote passed newborn screening and had normal hearing thresholds up to 3 years of age, which then deteriorated to a precipitous loss >1 kHz during the first decade. Our study suggests that genetic testing may be necessary to identify at-risk children in time to prevent speech, language and developmental delay.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-016-1746-7) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect

et al. 2016

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“…The maximum pathogenicity score (PS) was 6, and we considered those variants with a PS >4 as likely pathogenic (5). In addition, variants were evaluated in terms of mode of inheritance (i.e., recessive vs. dominant), phenotype (i.e., enlarged vestibular aqueduct, SLC24A4 ; delayed motor milestones, Usher syndrome type 1), and audioprofile using AudioGene (11). …”

Section: Methodsmentioning

confidence: 99%

Comprehensive genetic testing with ethnic‐specific filtering by allele frequency in a Japanese hearing‐loss population

et al. 2015

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Recent advances in targeted genomic enrichment with massively parallel sequencing (TGE+MPS) have made comprehensive genetic testing for non-syndromic hearing loss (NSHL) possible. After excluding NSHL subjects with causative mutations in GJB2 and the MT-RNR1 (1555A>G) variant by Sanger sequencing, we completed TGE+MPS on 194 probands with presumed NSHL identified across Japan. We used both publicly available minor allele frequency (MAF) datasets and ethnic-specific MAF filtering against an in-house database of 200 normal-hearing Japanese controls. Ethnic-specific MAF filtering allowed us to re-categorize as common 203 variants otherwise annotated as rare or novel in non-Japanese ethnicities. This step minimizes false-positive results and improves the annotation of identified variants. Causative variants were identified in 27% of probands with solve rates of 35%, 35% and 19% for dominant, recessive and sporadic NSHL, respectively. Mutations in MYO15A and CDH23 follow GJB2 as the frequent causes of recessive NSHL; copy number variations in STRC are a major cause of mild-to-moderate NSHL. Ethnic-specific filtering by allele frequency is essential to optimize the interpretation of genetic data.

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“…The analysis of audiometric profiles over a range of frequencies to describe phenotypic definitions may lead to the identification of underlying genotypes associated with a subset of cochlear genes (Hildebrand et al, 2009). Notched configurations are not included in their current Audiogene model (http://audiogene.eng.uiowa.edu/), nor in the European Union GENDEAF recommendations.…”

Section: Introductionmentioning

confidence: 99%

Feasibility of a bilateral 4000–6000 Hz notch as a phenotype for genetic association analysis

Phillips

Richter

Teglas

et al. 2015

International Journal of Audiology

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Objective Noise-induced hearing loss (NIHL) is a worldwide health problem and a growing concern among young people. Although some people appear to be more susceptible to NIHL, genetic association studies lack a specific phenotype. We tested the feasibility of a bilateral 4000–6000 Hz audiometric notch as a phenotype for identifying genetic contributions to hearing loss in young adults. Design A case-control-control study was conducted to examine selected SNPs in 52 genes previously associated with hearing loss and/or expressed in the cochlea. A notch was defined as a minimum of a 15-dB drop at 4000–6000 Hz from the previous best threshold with a 5-dB ‘recovery’ at 8000 Hz. Study sample Participants were 252 individuals of European descent taken from a population of 640 young adults who are students of classical music. Participants were grouped as No-notch (NN), Unilateral Notch (UN), or Bilateral Notch (BN). Results The strongest evidence of a genetic association with the 4000–6000 Hz notch was a nonsynonymous SNP variant in the ESRR? gene (rs61742642:C>T, P386S). Carriers of the minor allele accounted for 26% of all bilateral losses. Conclusion This study indicates that the 4000–6000 Hz bilateral notch is a feasible phenotype for identifying genetic susceptibility to hearing loss.

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A Contemporary Review of AudioGene audioprofiling: A machine‐based candidate gene prediction tool for autosomal dominant nonsyndromic hearing loss

Cited by 39 publications

References 7 publications

A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect

A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect

Comprehensive genetic testing with ethnic‐specific filtering by allele frequency in a Japanese hearing‐loss population

Feasibility of a bilateral 4000–6000 Hz notch as a phenotype for genetic association analysis

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