Hearing loss is one of the most common birth defects,with inherited genetic defects play an important role,contributing to about 60%of deafness occurring in infants.However,hearing impairment is genetically heterogene...Hearing loss is one of the most common birth defects,with inherited genetic defects play an important role,contributing to about 60%of deafness occurring in infants.However,hearing impairment is genetically heterogeneous,with both common and rare forms occurring due to mutations in estimated 500 genes.Due to the large number and presumably low mutation frequencies of those genes,it would be highly expensive and time-consuming to address this issue by conventional gene-by-gene Sanger sequencing.Next-generation sequencing is a revolutionary technology that allows the simultaneous screening of mutations in a large number of genes.It is cost effective compared to classical strategies of linkage analysis and direct sequencing when the number or size of genes is large,and thus has become a highly efficient strategy for identifying novel causative genes and mutations involved in heritable disease.In this review, we describe major NGS methodologies currently used for genetic disorders and highlight applications of these technologies in studies of molecular diagnosis and the discovery of genes implicated in non-syndromic hearing loss.展开更多
Hearing loss (HL) is the most common sensory disorder, affecting all age groups, ethnicities, and gen-ders. According to World Health Organization (WHO) estimates in 2005, 278 million people worldwide have moderate to...Hearing loss (HL) is the most common sensory disorder, affecting all age groups, ethnicities, and gen-ders. According to World Health Organization (WHO) estimates in 2005, 278 million people worldwide have moderate to profound HL in both ears. Results of the 2002 National Health Interview Survey indicate that nearly 31 million of all non-institutionalized adults (aged 18 and over) in the United States have trouble hearing. Epidemiological studies have estimated that approximately 50%of profound HL can be attributed to genetic causes. With over 60 genes implicated in nonsyndromic hearing loss, it is also an extremely het-erogeneous trait. Recent progress in identifying genes responsible for hearing loss enables otolaryngologists and other clinicians to apply molecular diagnosis by genetic testing. The advent of the $1000 genome has the potential to revolutionize the identification of genes and their mutations underlying genetic disorders. This is especially true for extremely heterogeneous Mendelian conditions such as deafness, where the muta-tion, and indeed the gene, may be private. The recent technological advances in target-enrichment methods and next generation sequencing offer a unique opportunity to break through the barriers of limitations im-posed by gene arrays. These approaches now allow for the complete analysis of all known deafness-causing genes and will result in a new wave of discoveries of the remaining genes for Mendelian disorders. This re-view focuses on describing genotype-phenotype correlations of the most frequent genes including GJB2, which is responsible for more than half of cases, followed by other common genes and on discussing the im-pact of genomic advances for comprehensive genetic testing and gene discovery in hereditary hearing loss.展开更多
BACKGROUND Variants in the MYO7A gene commonly result in Usher syndrome,and in rare cases lead to autosomal dominant non-syndromic deafness(DFNA11).Currently,only nine variants have been reported to be responsible for...BACKGROUND Variants in the MYO7A gene commonly result in Usher syndrome,and in rare cases lead to autosomal dominant non-syndromic deafness(DFNA11).Currently,only nine variants have been reported to be responsible for DFNA11 and their clinical phenotypes are not identical.Here we present a novel variant causing DFNA11 identified in a three-generation Chinese family.CASE SUMMARY The proband was a 53-year-old Han male who presented with post-lingual bilateral symmetrical moderate sensorineural hearing loss.We learned from the patient’s medical history collection that multiple family members also had similar hearing loss,generally occurring around the age of 40.Subsequent investigation by high-throughput sequencing identified a novel MYO7A variant.To provide evidence supporting that this variant is responsible for the hearing loss in the studied family,we performed Sanger sequencing on 11 family members and found that the variant co-segregated with the deafness phenotype.In addition,the clinical manifestation of the 11 affected family members was found to be lateonset bilateral slowly progressive hearing loss,inherited in this family in an autosomal dominant manner.None of the affected family members had visual impairment or vestibular symptoms;therefore,we believe that this novel MYO7A variant is responsible for the rare DFNA11 in this family.CONCLUSION We report a novel variant leading to DFNA11 which further enriches the collection of MYO7A variants,and our review of the nine previous variants that have been identified to cause DFNA11 provides a reference for clinical genetic counseling.展开更多
In this article,the mechanism of inheritance behind inherited hearing loss and genetic susceptibilityin noise-induced hearing loss are reviewed.Conventional treatments for sensorineural hearing loss(SNHL),i.e.hearing ...In this article,the mechanism of inheritance behind inherited hearing loss and genetic susceptibilityin noise-induced hearing loss are reviewed.Conventional treatments for sensorineural hearing loss(SNHL),i.e.hearing aid and cochlear implant,are effective for some cases,but not without limitations.For example,they provide little benefit for patients of profound SNHL or neural hearing loss,especially when the hearing loss is in poor dynamic range and with low frequency resolution.We emphasize the most recent evidence-based treatment in this field,which includes gene therapy and allotransplantation of stem cells.Their promising results have shown that they might be options of treatment for profound SNHL and neural hearing loss.Although some treatments are still at the experimental stage,it is helpful to be aware of the novel therapies and endeavour to explore the feasibility of their clinical application.展开更多
Dear Editor,Actins are a family of essential cytoskeletal proteins involved in nearly all cellular processes（Lambrechts et al.,2004）.Of the six human genes that encode actins,only ACTG1and ACTB are ubiquitously expr...Dear Editor,Actins are a family of essential cytoskeletal proteins involved in nearly all cellular processes（Lambrechts et al.,2004）.Of the six human genes that encode actins,only ACTG1and ACTB are ubiquitously expressed.ACTG1（OMIM#604717）,which is linked to the DFNA20/26 locus,wasidentified in autosomal dominant, non-syndromic hearing loss （NSHL） cases （Baek et al., 2012; Liu et al., 2008; Park et al., 2013; Yuan et al., 2016）. In addition, some ACTG1 （OMIM #614583） mutations are associated with Baraitser-Winter syndrome, which is characterized by developmental delay, facial dysmorphologies, brain malformations, colobomas, and variable hearing loss （Riviere et al., 2012）.展开更多
Non-syndromic hearing loss(NSHL)is a common defect in humans.Variants of MARVELD2 at the DFNB49 locus have been shown to cause bilateral,moderate to profound NSHL.However,the role of MARVELD2 in NSHL susceptibility in...Non-syndromic hearing loss(NSHL)is a common defect in humans.Variants of MARVELD2 at the DFNB49 locus have been shown to cause bilateral,moderate to profound NSHL.However,the role of MARVELD2 in NSHL susceptibility in the Chinese population has not been studied.Here we conducted a case-control study in an eastern Chinese population to profile the spectrum and frequency of MARVELD2 variants,as well as the association of MARVELD2 gene variants with NSHL.Our results showed that variants identified in the Chinese population are significantly different from those reported in Slovak,Hungarian,and Czech Roma,as well as Pakistani families.We identified 11 variants in a cohort of 283 NSHL cases.展开更多
KCNQ4 gene mutation can lead to deafness non-syndromic autosomal dominant 2A,which is a type of autosomal dominant non-syndromic hearing loss.Deafness non-syndromic autosomal dominant 2A patients with KCNQ4 gene mutat...KCNQ4 gene mutation can lead to deafness non-syndromic autosomal dominant 2A,which is a type of autosomal dominant non-syndromic hearing loss.Deafness non-syndromic autosomal dominant 2A patients with KCNQ4 gene mutation usually present with symmetrical,delayed,progressive high-frequency-affected hearing loss,which eventually can involve all frequencies.In this article,we comprehensively reviewed the research on the role and function of KCNQ4 gene in genetic hearing loss.We discussed the pathological and physiological mechanisms of KCNQ4 gene and the related clinical phenotypes of KCNQ4 gene mutations.We also reviewed the latest developments in the treatment of KCNQ4 gene mutation-related genetic hearing loss,including selective potassium channel activation drugs and gene therapy.展开更多
Hearing impairment is considered as the most prevalent impairment worldwide. Almost 600 million people in the world suffer from mild or moderate hearing impairment, an estimated 10% of the human population. Genetic fa...Hearing impairment is considered as the most prevalent impairment worldwide. Almost 600 million people in the world suffer from mild or moderate hearing impairment, an estimated 10% of the human population. Genetic factors play an important role in the pathogenesis of this disorder. Hereditary hearing loss is divided into syndromic hearing loss （associated with other anomalies） and non-syndromic hearing loss （not associated with other anomalies）. Approximately 80% of genetic deafness is non-syndromic. On the basis of the frequency of hearing loss, hereditary non-syndromic hearing loss can be divided into high-, mid-, low-, and total-frequency hearing loss. An audiometric finding of mid-frequency sensorineural hearing loss, or a ＂bowl-shaped＂ audiogram, is uncommon. Up to now, merely 7 loci have been linked to mid-frequency hearing loss. Only four genetic mid- frequency deafness genes, namely, DFNA10 （EYA4）, DFNA8/12 （TECTA）, DFNA13 （COLIIA2）, DFNA44 （CCDC50）, have been reported to date. This review summarizes the research progress of the four genes to draw attention to mid-frequency deafness genes.展开更多
基金supported by grants from the Project of the National Natural Science Foundation of China(Grant Nos.30801285,81230020,81200751,81070792,81000415, 81360159)grants from China Postdoctoral Science Foundation(No.2012M,2013T52187860947)a grant from Minister of Science and Technology of China(2012BAI09B02)
文摘Hearing loss is one of the most common birth defects,with inherited genetic defects play an important role,contributing to about 60%of deafness occurring in infants.However,hearing impairment is genetically heterogeneous,with both common and rare forms occurring due to mutations in estimated 500 genes.Due to the large number and presumably low mutation frequencies of those genes,it would be highly expensive and time-consuming to address this issue by conventional gene-by-gene Sanger sequencing.Next-generation sequencing is a revolutionary technology that allows the simultaneous screening of mutations in a large number of genes.It is cost effective compared to classical strategies of linkage analysis and direct sequencing when the number or size of genes is large,and thus has become a highly efficient strategy for identifying novel causative genes and mutations involved in heritable disease.In this review, we describe major NGS methodologies currently used for genetic disorders and highlight applications of these technologies in studies of molecular diagnosis and the discovery of genes implicated in non-syndromic hearing loss.
文摘Hearing loss (HL) is the most common sensory disorder, affecting all age groups, ethnicities, and gen-ders. According to World Health Organization (WHO) estimates in 2005, 278 million people worldwide have moderate to profound HL in both ears. Results of the 2002 National Health Interview Survey indicate that nearly 31 million of all non-institutionalized adults (aged 18 and over) in the United States have trouble hearing. Epidemiological studies have estimated that approximately 50%of profound HL can be attributed to genetic causes. With over 60 genes implicated in nonsyndromic hearing loss, it is also an extremely het-erogeneous trait. Recent progress in identifying genes responsible for hearing loss enables otolaryngologists and other clinicians to apply molecular diagnosis by genetic testing. The advent of the $1000 genome has the potential to revolutionize the identification of genes and their mutations underlying genetic disorders. This is especially true for extremely heterogeneous Mendelian conditions such as deafness, where the muta-tion, and indeed the gene, may be private. The recent technological advances in target-enrichment methods and next generation sequencing offer a unique opportunity to break through the barriers of limitations im-posed by gene arrays. These approaches now allow for the complete analysis of all known deafness-causing genes and will result in a new wave of discoveries of the remaining genes for Mendelian disorders. This re-view focuses on describing genotype-phenotype correlations of the most frequent genes including GJB2, which is responsible for more than half of cases, followed by other common genes and on discussing the im-pact of genomic advances for comprehensive genetic testing and gene discovery in hereditary hearing loss.
文摘BACKGROUND Variants in the MYO7A gene commonly result in Usher syndrome,and in rare cases lead to autosomal dominant non-syndromic deafness(DFNA11).Currently,only nine variants have been reported to be responsible for DFNA11 and their clinical phenotypes are not identical.Here we present a novel variant causing DFNA11 identified in a three-generation Chinese family.CASE SUMMARY The proband was a 53-year-old Han male who presented with post-lingual bilateral symmetrical moderate sensorineural hearing loss.We learned from the patient’s medical history collection that multiple family members also had similar hearing loss,generally occurring around the age of 40.Subsequent investigation by high-throughput sequencing identified a novel MYO7A variant.To provide evidence supporting that this variant is responsible for the hearing loss in the studied family,we performed Sanger sequencing on 11 family members and found that the variant co-segregated with the deafness phenotype.In addition,the clinical manifestation of the 11 affected family members was found to be lateonset bilateral slowly progressive hearing loss,inherited in this family in an autosomal dominant manner.None of the affected family members had visual impairment or vestibular symptoms;therefore,we believe that this novel MYO7A variant is responsible for the rare DFNA11 in this family.CONCLUSION We report a novel variant leading to DFNA11 which further enriches the collection of MYO7A variants,and our review of the nine previous variants that have been identified to cause DFNA11 provides a reference for clinical genetic counseling.
文摘In this article,the mechanism of inheritance behind inherited hearing loss and genetic susceptibilityin noise-induced hearing loss are reviewed.Conventional treatments for sensorineural hearing loss(SNHL),i.e.hearing aid and cochlear implant,are effective for some cases,but not without limitations.For example,they provide little benefit for patients of profound SNHL or neural hearing loss,especially when the hearing loss is in poor dynamic range and with low frequency resolution.We emphasize the most recent evidence-based treatment in this field,which includes gene therapy and allotransplantation of stem cells.Their promising results have shown that they might be options of treatment for profound SNHL and neural hearing loss.Although some treatments are still at the experimental stage,it is helpful to be aware of the novel therapies and endeavour to explore the feasibility of their clinical application.
基金supported by the National Natural Science Foundation of China(81530032)the National Key Basic Research Program of China(2014CB943001)
文摘Dear Editor,Actins are a family of essential cytoskeletal proteins involved in nearly all cellular processes（Lambrechts et al.,2004）.Of the six human genes that encode actins,only ACTG1and ACTB are ubiquitously expressed.ACTG1（OMIM#604717）,which is linked to the DFNA20/26 locus,wasidentified in autosomal dominant, non-syndromic hearing loss （NSHL） cases （Baek et al., 2012; Liu et al., 2008; Park et al., 2013; Yuan et al., 2016）. In addition, some ACTG1 （OMIM #614583） mutations are associated with Baraitser-Winter syndrome, which is characterized by developmental delay, facial dysmorphologies, brain malformations, colobomas, and variable hearing loss （Riviere et al., 2012）.
基金Project supported by the National Basic Research Priorities Program of China(Nos.2014CB541702 and 2014CB541704)the National Natural Science Foundation of China(Nos.8147068 5?yand 81600817)the Zhejiang Provincial Public Welfare Technology Applied Research Project(No.2016C33148),China
文摘Non-syndromic hearing loss(NSHL)is a common defect in humans.Variants of MARVELD2 at the DFNB49 locus have been shown to cause bilateral,moderate to profound NSHL.However,the role of MARVELD2 in NSHL susceptibility in the Chinese population has not been studied.Here we conducted a case-control study in an eastern Chinese population to profile the spectrum and frequency of MARVELD2 variants,as well as the association of MARVELD2 gene variants with NSHL.Our results showed that variants identified in the Chinese population are significantly different from those reported in Slovak,Hungarian,and Czech Roma,as well as Pakistani families.We identified 11 variants in a cohort of 283 NSHL cases.
基金supported by the grants of the National Natural Science Foundation of China(Major Project No.81830028,Youths Program Nos.81900950 and 81900951).
文摘KCNQ4 gene mutation can lead to deafness non-syndromic autosomal dominant 2A,which is a type of autosomal dominant non-syndromic hearing loss.Deafness non-syndromic autosomal dominant 2A patients with KCNQ4 gene mutation usually present with symmetrical,delayed,progressive high-frequency-affected hearing loss,which eventually can involve all frequencies.In this article,we comprehensively reviewed the research on the role and function of KCNQ4 gene in genetic hearing loss.We discussed the pathological and physiological mechanisms of KCNQ4 gene and the related clinical phenotypes of KCNQ4 gene mutations.We also reviewed the latest developments in the treatment of KCNQ4 gene mutation-related genetic hearing loss,including selective potassium channel activation drugs and gene therapy.
文摘Hearing impairment is considered as the most prevalent impairment worldwide. Almost 600 million people in the world suffer from mild or moderate hearing impairment, an estimated 10% of the human population. Genetic factors play an important role in the pathogenesis of this disorder. Hereditary hearing loss is divided into syndromic hearing loss （associated with other anomalies） and non-syndromic hearing loss （not associated with other anomalies）. Approximately 80% of genetic deafness is non-syndromic. On the basis of the frequency of hearing loss, hereditary non-syndromic hearing loss can be divided into high-, mid-, low-, and total-frequency hearing loss. An audiometric finding of mid-frequency sensorineural hearing loss, or a ＂bowl-shaped＂ audiogram, is uncommon. Up to now, merely 7 loci have been linked to mid-frequency hearing loss. Only four genetic mid- frequency deafness genes, namely, DFNA10 （EYA4）, DFNA8/12 （TECTA）, DFNA13 （COLIIA2）, DFNA44 （CCDC50）, have been reported to date. This review summarizes the research progress of the four genes to draw attention to mid-frequency deafness genes.
文摘目的分析南宁地区新生儿常见耳聋基因携带情况和突变类型,探讨汉族与壮族之间的差异。方法采用导流杂交技术对2017年8月至2021年4月在广西壮族自治区民族医院出生的6698例新生儿进行GJB2、SLC26A4、mt DNA和GJB3基因的13个突变位点检测,分析耳聋基因的总体检出率及突变位点的分布情况,对壮汉两民族进行统计分析。结果耳聋基因筛查总阳性119例,总体检出率为1.78%,汉族为2.02%,壮族为1.63%,差异无统计学意义(P=0.253)。GJB2基因为主要突变基因,总体检出率为1.00%,汉族1.11%,壮族1.00%,两者差异无统计学意义(P=0.680)。其次是SLC26A4基因0.48%,mt DNA0.27%和GJB30.03%,在汉族与壮族间差异无统计学意义(P>0.05)。c.235 del C是主要突变位点,检出率为0.875%,在汉族与壮族间差异无统计学意义(P>0.05)。SLC26A4基因的c.919-2A>G突变位点的检出率汉族高于壮族,差异有统计学意义(P=0.028)。结论GJB2基因为新生儿常见耳聋主要突变基因;汉族c.919-2A>G突变位点的检出率高于壮族。
