Study of complex structural variations of X-linked deafness-2 based on single-molecule sequencing
X-linked deafness-2 (DFNX2) is cochlear incomplete partition type III (IP-III), one of inner ear malformations characterized by an abnormally wide opening in the bone separating the basal turn of the cochlea from the internal auditory canal, fixation of the stapes and cerebrospinal fluid (CSF) gushe...
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| creator | Jiang, Yi Wu, Lihua Huang, Shasha Li, Pidong Gao, Bo Yuan, Yongyi Zhang, Siwen Yu, Guoliang Gao, Yong Wu, Hao Dai, Pu |
| description | X-linked deafness-2 (DFNX2) is cochlear incomplete partition type III (IP-III), one of inner ear malformations characterized by an abnormally wide opening in the bone separating the basal turn of the cochlea from the internal auditory canal, fixation of the stapes and cerebrospinal fluid (CSF) gusher upon stapedectomy or cochleostomy. The causative gene of DFNX2 was POU3F4. To investigate the genetic causes of DFNX2 and compare the efficiency of different sequencing methods, 12 unrelated patients were enrolled in the present study. Targeted next-generation sequencing (NGS) and long-read sequencing were used to analyze the genetic etiology of DFNX2. Six variants of POU3F4 were identified in this cohort by NGS. Three patients with a negative diagnosis based on NGS were enrolled in further long-read sequencing. Two of them were all found to carry structural variations (SVs) on chromosome X, consisting of an 870-kb deletion (DEL) at upstream of POU3F4 and an 8-Mb inversion (INV). The 870-kb DEL may have been due to non-homologous end joining (NHEJ), while non-allelic homologous recombination (NAHR) within a single chromatid may have accounted for the 8-Mb INV. Common POU3F4 mutations in DFNX2 included point mutations, small insertions and deletions (INDELs), and exon mutations, which can be detected by Sanger sequencing and NGS. Single-molecule long-read sequencing constitutes an additional and valuable method for accurate detection of pathogenic SVs in IP-III patients with negative NGS results. |
| doi_str_mv | 10.1042/BSR20203740 |
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The causative gene of DFNX2 was POU3F4. To investigate the genetic causes of DFNX2 and compare the efficiency of different sequencing methods, 12 unrelated patients were enrolled in the present study. Targeted next-generation sequencing (NGS) and long-read sequencing were used to analyze the genetic etiology of DFNX2. Six variants of POU3F4 were identified in this cohort by NGS. Three patients with a negative diagnosis based on NGS were enrolled in further long-read sequencing. Two of them were all found to carry structural variations (SVs) on chromosome X, consisting of an 870-kb deletion (DEL) at upstream of POU3F4 and an 8-Mb inversion (INV). The 870-kb DEL may have been due to non-homologous end joining (NHEJ), while non-allelic homologous recombination (NAHR) within a single chromatid may have accounted for the 8-Mb INV. Common POU3F4 mutations in DFNX2 included point mutations, small insertions and deletions (INDELs), and exon mutations, which can be detected by Sanger sequencing and NGS. Single-molecule long-read sequencing constitutes an additional and valuable method for accurate detection of pathogenic SVs in IP-III patients with negative NGS results.</description><identifier>ISSN: 0144-8463</identifier><identifier>EISSN: 1573-4935</identifier><identifier>DOI: 10.1042/BSR20203740</identifier><identifier>PMID: 33860785</identifier><language>eng</language><publisher>England: Portland Press Ltd The Biochemical Society</publisher><subject>Biotechnology ; Cerebrospinal fluid ; Child ; Child, Preschool ; Chromosome deletion ; Cochlea ; Deafness ; DNA Mutational Analysis ; DNA, Chromosomes & Chromosomal Structure ; Ear ; Ear canal ; Families & family life ; Gene Expression & Regulation ; Genes ; Genetic Diseases, X-Linked - diagnosis ; Genetic Diseases, X-Linked - genetics ; Genetic Diseases, X-Linked - physiopathology ; Genetic Predisposition to Disease ; Genetic testing ; Genomes ; Genomics ; Hearing - genetics ; Hearing loss ; Hearing Loss, Conductive - diagnosis ; Hearing Loss, Conductive - genetics ; Hearing Loss, Conductive - physiopathology ; Hearing Loss, Sensorineural - diagnosis ; Hearing Loss, Sensorineural - genetics ; Hearing Loss, Sensorineural - physiopathology ; High-Throughput Nucleotide Sequencing ; Homologous recombination ; Homology ; Humans ; Infant ; Inner ear ; Leukocytes ; Male ; Mutation ; Next-generation sequencing ; Non-homologous end joining ; Phenotype ; Polymerase chain reaction ; POU Domain Factors - genetics ; Predictive Value of Tests ; Reproducibility of Results ; Single Molecule Imaging</subject><ispartof>Bioscience reports, 2021-06, Vol.41 (6)</ispartof><rights>2021 The Author(s).</rights><rights>2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). 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The causative gene of DFNX2 was POU3F4. To investigate the genetic causes of DFNX2 and compare the efficiency of different sequencing methods, 12 unrelated patients were enrolled in the present study. Targeted next-generation sequencing (NGS) and long-read sequencing were used to analyze the genetic etiology of DFNX2. Six variants of POU3F4 were identified in this cohort by NGS. Three patients with a negative diagnosis based on NGS were enrolled in further long-read sequencing. Two of them were all found to carry structural variations (SVs) on chromosome X, consisting of an 870-kb deletion (DEL) at upstream of POU3F4 and an 8-Mb inversion (INV). The 870-kb DEL may have been due to non-homologous end joining (NHEJ), while non-allelic homologous recombination (NAHR) within a single chromatid may have accounted for the 8-Mb INV. Common POU3F4 mutations in DFNX2 included point mutations, small insertions and deletions (INDELs), and exon mutations, which can be detected by Sanger sequencing and NGS. Single-molecule long-read sequencing constitutes an additional and valuable method for accurate detection of pathogenic SVs in IP-III patients with negative NGS results.</description><subject>Biotechnology</subject><subject>Cerebrospinal fluid</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Chromosome deletion</subject><subject>Cochlea</subject><subject>Deafness</subject><subject>DNA Mutational Analysis</subject><subject>DNA, Chromosomes & Chromosomal Structure</subject><subject>Ear</subject><subject>Ear canal</subject><subject>Families & family life</subject><subject>Gene Expression & Regulation</subject><subject>Genes</subject><subject>Genetic Diseases, X-Linked - diagnosis</subject><subject>Genetic Diseases, X-Linked - genetics</subject><subject>Genetic Diseases, X-Linked - physiopathology</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetic testing</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Hearing - genetics</subject><subject>Hearing loss</subject><subject>Hearing Loss, Conductive - diagnosis</subject><subject>Hearing Loss, Conductive - genetics</subject><subject>Hearing Loss, Conductive - physiopathology</subject><subject>Hearing Loss, Sensorineural - diagnosis</subject><subject>Hearing Loss, Sensorineural - genetics</subject><subject>Hearing Loss, Sensorineural - physiopathology</subject><subject>High-Throughput Nucleotide Sequencing</subject><subject>Homologous recombination</subject><subject>Homology</subject><subject>Humans</subject><subject>Infant</subject><subject>Inner ear</subject><subject>Leukocytes</subject><subject>Male</subject><subject>Mutation</subject><subject>Next-generation sequencing</subject><subject>Non-homologous end joining</subject><subject>Phenotype</subject><subject>Polymerase chain reaction</subject><subject>POU Domain Factors - genetics</subject><subject>Predictive Value of Tests</subject><subject>Reproducibility of Results</subject><subject>Single Molecule Imaging</subject><issn>0144-8463</issn><issn>1573-4935</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkUtLHUEQhRtJiDc3WWUvA9kEwpjqxzx6EzBioiAImkV2TU1PjRnt6b7pnhH99-mLD9RVwamPw6k6jH3isM9BiW8_Ls4FCJCNgh224lUjS6Vl9YatgCtVtqqWu-x9SlcAkBfqHduVsq2haasVw4t56e-KMBQ2TBtHt0Wa42LnJaIrbjCOOI_Bpy3wp3Sjv6a-6AkHTymVougwZSH4Io3-0lE5BUd2cVQk-reQt1n9wN4O6BJ9fJhrdv7z6PfhcXl69uvk8OC0tAr0XGLfC62Q60FxXTVWyK7Dlne8BYtQge1Uixyp7ogTIYqm7utG11yB7OSafb833SzdRL0lP-cDzCaOE8Y7E3A0Lzd-_Gsuw41puZZ1tlizLw8GMeTkaTbTmCw5h57CkoyouMovA60y-vkVehWW6PNtRmjZaNWC3FJf7ykbQ0qRhqcwHMy2N_Ost0zvPc__xD4WJf8DgwuUXQ</recordid><startdate>20210625</startdate><enddate>20210625</enddate><creator>Jiang, Yi</creator><creator>Wu, Lihua</creator><creator>Huang, Shasha</creator><creator>Li, Pidong</creator><creator>Gao, Bo</creator><creator>Yuan, Yongyi</creator><creator>Zhang, Siwen</creator><creator>Yu, Guoliang</creator><creator>Gao, Yong</creator><creator>Wu, Hao</creator><creator>Dai, Pu</creator><general>Portland Press Ltd The Biochemical Society</general><general>Portland Press Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7QO</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PATMY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PYCSY</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3725-0148</orcidid></search><sort><creationdate>20210625</creationdate><title>Study of complex structural variations of X-linked deafness-2 based on single-molecule sequencing</title><author>Jiang, Yi ; Wu, Lihua ; Huang, Shasha ; Li, Pidong ; Gao, Bo ; Yuan, Yongyi ; Zhang, Siwen ; Yu, Guoliang ; Gao, Yong ; Wu, Hao ; Dai, Pu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c409t-add294a19f41957c23bba81b180ca050cb48a1ae6be1eeaa276d67961403b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Biotechnology</topic><topic>Cerebrospinal fluid</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Chromosome deletion</topic><topic>Cochlea</topic><topic>Deafness</topic><topic>DNA Mutational Analysis</topic><topic>DNA, Chromosomes & Chromosomal Structure</topic><topic>Ear</topic><topic>Ear canal</topic><topic>Families & family life</topic><topic>Gene Expression & Regulation</topic><topic>Genes</topic><topic>Genetic Diseases, X-Linked - diagnosis</topic><topic>Genetic Diseases, X-Linked - genetics</topic><topic>Genetic Diseases, X-Linked - physiopathology</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetic testing</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Hearing - genetics</topic><topic>Hearing loss</topic><topic>Hearing Loss, Conductive - diagnosis</topic><topic>Hearing Loss, Conductive - genetics</topic><topic>Hearing Loss, Conductive - physiopathology</topic><topic>Hearing Loss, Sensorineural - diagnosis</topic><topic>Hearing Loss, Sensorineural - genetics</topic><topic>Hearing Loss, Sensorineural - physiopathology</topic><topic>High-Throughput Nucleotide Sequencing</topic><topic>Homologous recombination</topic><topic>Homology</topic><topic>Humans</topic><topic>Infant</topic><topic>Inner ear</topic><topic>Leukocytes</topic><topic>Male</topic><topic>Mutation</topic><topic>Next-generation sequencing</topic><topic>Non-homologous end joining</topic><topic>Phenotype</topic><topic>Polymerase chain reaction</topic><topic>POU Domain Factors - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Bioscience reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jiang, Yi</au><au>Wu, Lihua</au><au>Huang, Shasha</au><au>Li, Pidong</au><au>Gao, Bo</au><au>Yuan, Yongyi</au><au>Zhang, Siwen</au><au>Yu, Guoliang</au><au>Gao, Yong</au><au>Wu, Hao</au><au>Dai, Pu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Study of complex structural variations of X-linked deafness-2 based on single-molecule sequencing</atitle><jtitle>Bioscience reports</jtitle><addtitle>Biosci Rep</addtitle><date>2021-06-25</date><risdate>2021</risdate><volume>41</volume><issue>6</issue><issn>0144-8463</issn><eissn>1573-4935</eissn><abstract>X-linked deafness-2 (DFNX2) is cochlear incomplete partition type III (IP-III), one of inner ear malformations characterized by an abnormally wide opening in the bone separating the basal turn of the cochlea from the internal auditory canal, fixation of the stapes and cerebrospinal fluid (CSF) gusher upon stapedectomy or cochleostomy. The causative gene of DFNX2 was POU3F4. To investigate the genetic causes of DFNX2 and compare the efficiency of different sequencing methods, 12 unrelated patients were enrolled in the present study. Targeted next-generation sequencing (NGS) and long-read sequencing were used to analyze the genetic etiology of DFNX2. Six variants of POU3F4 were identified in this cohort by NGS. Three patients with a negative diagnosis based on NGS were enrolled in further long-read sequencing. Two of them were all found to carry structural variations (SVs) on chromosome X, consisting of an 870-kb deletion (DEL) at upstream of POU3F4 and an 8-Mb inversion (INV). The 870-kb DEL may have been due to non-homologous end joining (NHEJ), while non-allelic homologous recombination (NAHR) within a single chromatid may have accounted for the 8-Mb INV. Common POU3F4 mutations in DFNX2 included point mutations, small insertions and deletions (INDELs), and exon mutations, which can be detected by Sanger sequencing and NGS. Single-molecule long-read sequencing constitutes an additional and valuable method for accurate detection of pathogenic SVs in IP-III patients with negative NGS results.</abstract><cop>England</cop><pub>Portland Press Ltd The Biochemical Society</pub><pmid>33860785</pmid><doi>10.1042/BSR20203740</doi><orcidid>https://orcid.org/0000-0002-3725-0148</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Biotechnology Cerebrospinal fluid Child Child, Preschool Chromosome deletion Cochlea Deafness DNA Mutational Analysis DNA, Chromosomes & Chromosomal Structure Ear Ear canal Families & family life Gene Expression & Regulation Genes Genetic Diseases, X-Linked - diagnosis Genetic Diseases, X-Linked - genetics Genetic Diseases, X-Linked - physiopathology Genetic Predisposition to Disease Genetic testing Genomes Genomics Hearing - genetics Hearing loss Hearing Loss, Conductive - diagnosis Hearing Loss, Conductive - genetics Hearing Loss, Conductive - physiopathology Hearing Loss, Sensorineural - diagnosis Hearing Loss, Sensorineural - genetics Hearing Loss, Sensorineural - physiopathology High-Throughput Nucleotide Sequencing Homologous recombination Homology Humans Infant Inner ear Leukocytes Male Mutation Next-generation sequencing Non-homologous end joining Phenotype Polymerase chain reaction POU Domain Factors - genetics Predictive Value of Tests Reproducibility of Results Single Molecule Imaging |
| title | Study of complex structural variations of X-linked deafness-2 based on single-molecule sequencing |
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