Abstract
BackgroundCopy number variations (CNVs) are the major type of structural variation in the human genome, and are more common than DNA sequence variations in populations. CNVs are important factors for human genetic and phenotypic diversity. Many CNVs have been associated with either resistance to diseases or identified as the cause of diseases. Currently little is known about the role of CNVs in causing deafness. CNVs are currently not analyzed by conventional genetic analysis methods to study deafness. Here we detected both DNA sequence variations and CNVs affecting 80 genes known to be required for normal hearing.MethodsCoding regions of the deafness genes were captured by a hybridization-based method and processed through the standard next-generation sequencing (NGS) protocol using the Illumina platform. Samples hybridized together in the same reaction were analyzed to obtain CNVs. A read depth based method was used to measure CNVs at the resolution of a single exon. Results were validated by the quantitative PCR (qPCR) based method.ResultsAmong 79 sporadic cases clinically diagnosed with sensorineural hearing loss, we identified previously-reported disease-causing sequence mutations in 16 cases. In addition, we identified a total of 97 CNVs (72 CNV gains and 25 CNV losses) in 27 deafness genes. The CNVs included homozygous deletions which may directly give rise to deleterious effects on protein functions known to be essential for hearing, as well as heterozygous deletions and CNV gains compounded with sequence mutations in deafness genes that could potentially harm gene functions.ConclusionsWe studied how CNVs in known deafness genes may result in deafness. Data provided here served as a basis to explain how CNVs disrupt normal functions of deafness genes. These results may significantly expand our understanding about how various types of genetic mutations cause deafness in humans.
Highlights
Copy number variations (CNVs) are the major type of structural variation in the human genome, and are more common than DNA sequence variations in populations
CNVs found by the next-generation sequencing (NGS) approach and validation results by quantitative polymerase chain reactions (PCR) (qPCR) Among the 80 deafness genes analyzed from the 79 patient samples, we identified a total of 97 CNVs
Among 15 randomly selected CNVs, we found that qPCR confirmed most (14 out of 15) of the CNVs found by the NGS method (Additional file 5: Table S3), suggesting that the ratios derived from the average read depth of the NGS data provided a reliable estimate of the CNVs in deafness genes
Summary
Copy number variations (CNVs) are the major type of structural variation in the human genome, and are more common than DNA sequence variations in populations. CNVs are important factors for human genetic and phenotypic diversity. CNVs are currently not analyzed by conventional genetic analysis methods to study deafness. We detected both DNA sequence variations and CNVs affecting 80 genes known to be required for normal hearing. Multiple factors, including ototoxic drug usage, noise exposure, and genetic mutations can cause hearing loss. The majority of human hearing loss cases (~70%), are attributed to genetic factors [1]. Large numbers of studies have identified many deafness genes whose functions are essential for normal hearing [2] (Additional file 1: Table S1). The diagnostic information could be used in the management and treatment of hearing loss as it identifies the root cause of deafness
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