Article

OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele

Department of Hearing and Speech Sciences, Vanderbilt University, Нашвилл, Michigan, United States
Journal of Medical Genetics (Impact Factor: 5.64). 08/2006; 43(7):576-81. DOI: 10.1136/jmg.2005.038612
Source: PubMed

ABSTRACT The majority of hearing loss in children can be accounted for by genetic causes. Non-syndromic hearing loss accounts for 80% of genetic hearing loss in children, with mutations in DFNB1/GJB2 being by far the most common cause. Among the second tier genetic causes of hearing loss in children are mutations in the DFNB9/OTOF gene.
In total, 65 recessive non-syndromic hearing loss families were screened by genotyping for association with the DFNB9/OTOF gene. Families with genotypes consistent with linkage or uninformative for linkage to this gene region were further screened for mutations in the 48 known coding exons of otoferlin.
Eight OTOF pathological variants were discovered in six families. Of these, Q829X was found in two families. We also noted 23 other coding variant, believed to have no pathology. A previously published missense allele I515T was found in the heterozygous state in an individual who was observed to be temperature sensitive for the auditory neuropathy phenotype.
Mutations in OTOF cause both profound hearing loss and a type of hearing loss where otoacoustic emissions are spared called auditory neuropathy.

0 Followers
 · 
83 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Resequencing of deafness related genes using GS FLX massive parallel sequencing of PCR amplicons spanning selected genes has previously been reported as a successful strategy to discover causal variants. The amplicon lengths were designed to be smaller than the sequencing read length of GS FLX technology, but are longer than Illumina sequencing technology read lengths. Fragmentation is thus required to sequence these amplicons using high throughput Illumina technology. Methods We performed Illumina sequencing in 4 patients on 563 multiplexed amplicons covering the exons of 15 genes involved in the hearing process. After exploring several fragmentation strategies, the amplicons were fragmented using Covaris sonication prior to library preparation. CLC genomic workbench was used to analyze the data. Results We achieve an excellent coverage with more than 99% of the amplicons bases covered. All variants that were previously validated using Sanger sequencing, were also called in this study. Variant calling revealed less false positive and false negative results compared to the previous study. For each patient, several variants were found that are reported by ClinVar as possible hearing loss variants. Conclusion Migration from GS FLX amplicon sequencing to Illumina amplicon sequencing is straightforward and leads to more accurate results. Electronic supplementary material The online version of this article (doi:10.1186/1756-0500-7-509) contains supplementary material, which is available to authorized users.
    BMC Research Notes 08/2014; 7(1):509. DOI:10.1186/1756-0500-7-509
  • [Show abstract] [Hide abstract]
    ABSTRACT: Permanent childhood sensorineural hearing loss, is one of the most common birth defects in developed countries. It is important to identify the aetiology of hearing loss for many reasons, as there may be important health surveillance implications particularly with syndromic causes. Non-syndromic sensorineural hearing loss is a highly heterogeneous genetic condition, meaning that it may be caused by any one of numerous genes, with very few phenotypic distinctions between the different genetic types. This has previously presented significant challenges for genetic testing. However, the introduction of new technologies should enable more comprehensive testing in the future, bringing significant benefits to more affected children and their families.
    Archives of Disease in Childhood 10/2014; DOI:10.1136/archdischild-2014-306099 · 2.91 Impact Factor
  • Source

Preview

Download
0 Downloads
Available from