Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patients
Background: Sensorineural hearing loss (SNHL) is the most common sensory impairment. Comprehensive next-generation sequencing (NGS) has become the standard for the etiological diagnosis of early-onset SNHL. However, accurate selection of target genomic regions (gene panel/exome/genome), analytical p...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de documento: | artigo |
| Data de publicação: | 2018 |
| País: | España |
| Recursos: | Conselleria de Salut i Consum del Govern de les Illes Balears |
| Repositório: | Docusalut |
| Idioma: | inglês |
| OAI Identifier: | oai:docusalut.com:20.500.13003/9217 |
| Acesso em linha: | https://hdl.handle.net/20.500.13003/9217 |
| Access Level: | Acceso aberto |
| Palavra-chave: | Middle Aged Infant Phenotype Male Infant, Newborn Female INDEL Mutation Young Adult Child Spain Adult Hearing Loss Humans Child, Preschool Adolescent Genomics High-Throughput Nucleotide Sequencing España Pérdida Auditiva Recién Nacido Femenino Lactante Adolescente Masculino Mutación INDEL Genómica Preescolar Humanos Persona de Mediana Edad Adulto Joven Fenotipo Secuenciación de Nucleótidos de Alto Rendimiento Niño Adulto Hereditary Hearing loss Precision Diagnostics NGS Gene panel |
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Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patientsCabanillas, RubenDineiro, MartaCifuentes, Guadalupe A.Castillo, DavidPruneda, Patricia C.Alvarez, RebecaSanchez-Duran, NoeliaCapin, RaquelPlasencia, AnaViejo-Diaz, MonicaGarcia-Gonzalez, NoeliaHernando, InesLlorente, Jose L.Reparaz-Andrade, AlfredoTorreira-Banzas, CristinaRosell-Andreo, JordiGovea-Callizo, NancyRamon Gomez-Martinez, JustoNunez-Batalla, FaustinoGarrote, Jose A.Mazon-Gutierrez, AngelCostales, MariaIsidoro-Garcia, MariaGarcia-Berrocal, BelenOrdonez, Gonzalo R.Cadinanos, JuanMiddle AgedInfantPhenotypeMaleInfant, NewbornFemaleINDEL MutationYoung AdultChildSpainAdultHearing LossHumansChild, PreschoolAdolescentGenomicsHigh-Throughput Nucleotide SequencingEspañaPérdida AuditivaRecién NacidoFemeninoLactanteAdolescenteMasculinoMutación INDELGenómicaPreescolarHumanosPersona de Mediana EdadAdulto JovenFenotipoSecuenciación de Nucleótidos de Alto RendimientoNiñoAdultoHereditaryHearing lossPrecisionDiagnosticsNGSGene panelBackground: Sensorineural hearing loss (SNHL) is the most common sensory impairment. Comprehensive next-generation sequencing (NGS) has become the standard for the etiological diagnosis of early-onset SNHL. However, accurate selection of target genomic regions (gene panel/exome/genome), analytical performance and variant interpretation remain relevant difficulties for its clinical implementation. Methods: We developed a novel NGS panel with 199 genes associated with non-syndromic and/or syndromic SNHL. We evaluated the analytical sensitivity and specificity of the panel on 1624 known single nucleotide variants (SNVs) and indels on a mixture of genomic DNA from 10 previously characterized lymphoblastoid cell lines, and analyzed 50 Spanish patients with presumed hereditary SNHL not caused by GJB2/GJB6, OTOF nor MT-RNR1 mutations. Results: The analytical sensitivity of the test to detect SNVs and indels on the DNA mixture from the cell lines was > 99.5%, with a specificity > 99.9%. The diagnostic yield on the SNHL patients was 42% (21/50): 47.6% (10/21) with autosomal recessive inheritance pattern (BSND, CDH23, MYO15A, STRC [n = 2], USH2A [n = 3], RDX, SLC26A4); 38.1% (8/21) autosomal dominant (ACTG1 [n = 3; 2 de novo], CHD7, GATA3 [de novo], MITF, P2RX2, SOX10), and 14.3% (3/21) X-linked (COL4A5 [de novo], POU3F4, PRPS1). 46.9% of causative variants (15/32) were not in the databases. 28.6% of genetically diagnosed cases (6/21) had previously undetected syndromes (Barakat, Usher type 2A [n = 3] and Waardenburg [n = 2]). 19% of genetic diagnoses (4/21) were attributable to large deletions/duplications (STRC deletion [n = 2]; partial CDH23 duplication; RDX exon 2 deletion). Conclusions: In the era of precision medicine, obtaining an etiologic diagnosis of SNHL is imperative. Here, we contribute to show that, with the right methodology, NGS can be transferred to the clinical practice, boosting the yield of SNHL genetic diagnosis to 50-60% (including GJB2/GJB6 alterations), improving diagnostic/prognostic accuracy, refining genetic and reproductive counseling and revealing clinically relevant undiagnosed syndromes.BMC20182018-07-0920182018-07-09research articlehttp://purl.org/coar/resource_type/c_2df8fbb1info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.13003/9217reponame:Docusalutinstname:Conselleria de Salut i Consum del Govern de les Illes BalearsInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:docusalut.com:20.500.13003/92172026-06-22T12:44:07Z |
| dc.title.none.fl_str_mv |
Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patients |
| title |
Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patients |
| spellingShingle |
Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patients Cabanillas, Ruben Middle Aged Infant Phenotype Male Infant, Newborn Female INDEL Mutation Young Adult Child Spain Adult Hearing Loss Humans Child, Preschool Adolescent Genomics High-Throughput Nucleotide Sequencing España Pérdida Auditiva Recién Nacido Femenino Lactante Adolescente Masculino Mutación INDEL Genómica Preescolar Humanos Persona de Mediana Edad Adulto Joven Fenotipo Secuenciación de Nucleótidos de Alto Rendimiento Niño Adulto Hereditary Hearing loss Precision Diagnostics NGS Gene panel |
| title_short |
Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patients |
| title_full |
Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patients |
| title_fullStr |
Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patients |
| title_full_unstemmed |
Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patients |
| title_sort |
Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patients |
| dc.creator.none.fl_str_mv |
Cabanillas, Ruben Dineiro, Marta Cifuentes, Guadalupe A. Castillo, David Pruneda, Patricia C. Alvarez, Rebeca Sanchez-Duran, Noelia Capin, Raquel Plasencia, Ana Viejo-Diaz, Monica Garcia-Gonzalez, Noelia Hernando, Ines Llorente, Jose L. Reparaz-Andrade, Alfredo Torreira-Banzas, Cristina Rosell-Andreo, Jordi Govea-Callizo, Nancy Ramon Gomez-Martinez, Justo Nunez-Batalla, Faustino Garrote, Jose A. Mazon-Gutierrez, Angel Costales, Maria Isidoro-Garcia, Maria Garcia-Berrocal, Belen Ordonez, Gonzalo R. Cadinanos, Juan |
| author |
Cabanillas, Ruben |
| author_facet |
Cabanillas, Ruben Dineiro, Marta Cifuentes, Guadalupe A. Castillo, David Pruneda, Patricia C. Alvarez, Rebeca Sanchez-Duran, Noelia Capin, Raquel Plasencia, Ana Viejo-Diaz, Monica Garcia-Gonzalez, Noelia Hernando, Ines Llorente, Jose L. Reparaz-Andrade, Alfredo Torreira-Banzas, Cristina Rosell-Andreo, Jordi Govea-Callizo, Nancy Ramon Gomez-Martinez, Justo Nunez-Batalla, Faustino Garrote, Jose A. Mazon-Gutierrez, Angel Costales, Maria Isidoro-Garcia, Maria Garcia-Berrocal, Belen Ordonez, Gonzalo R. Cadinanos, Juan |
| author_role |
author |
| author2 |
Dineiro, Marta Cifuentes, Guadalupe A. Castillo, David Pruneda, Patricia C. Alvarez, Rebeca Sanchez-Duran, Noelia Capin, Raquel Plasencia, Ana Viejo-Diaz, Monica Garcia-Gonzalez, Noelia Hernando, Ines Llorente, Jose L. Reparaz-Andrade, Alfredo Torreira-Banzas, Cristina Rosell-Andreo, Jordi Govea-Callizo, Nancy Ramon Gomez-Martinez, Justo Nunez-Batalla, Faustino Garrote, Jose A. Mazon-Gutierrez, Angel Costales, Maria Isidoro-Garcia, Maria Garcia-Berrocal, Belen Ordonez, Gonzalo R. Cadinanos, Juan |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
|
| dc.subject.none.fl_str_mv |
Middle Aged Infant Phenotype Male Infant, Newborn Female INDEL Mutation Young Adult Child Spain Adult Hearing Loss Humans Child, Preschool Adolescent Genomics High-Throughput Nucleotide Sequencing España Pérdida Auditiva Recién Nacido Femenino Lactante Adolescente Masculino Mutación INDEL Genómica Preescolar Humanos Persona de Mediana Edad Adulto Joven Fenotipo Secuenciación de Nucleótidos de Alto Rendimiento Niño Adulto Hereditary Hearing loss Precision Diagnostics NGS Gene panel |
| topic |
Middle Aged Infant Phenotype Male Infant, Newborn Female INDEL Mutation Young Adult Child Spain Adult Hearing Loss Humans Child, Preschool Adolescent Genomics High-Throughput Nucleotide Sequencing España Pérdida Auditiva Recién Nacido Femenino Lactante Adolescente Masculino Mutación INDEL Genómica Preescolar Humanos Persona de Mediana Edad Adulto Joven Fenotipo Secuenciación de Nucleótidos de Alto Rendimiento Niño Adulto Hereditary Hearing loss Precision Diagnostics NGS Gene panel |
| description |
Background: Sensorineural hearing loss (SNHL) is the most common sensory impairment. Comprehensive next-generation sequencing (NGS) has become the standard for the etiological diagnosis of early-onset SNHL. However, accurate selection of target genomic regions (gene panel/exome/genome), analytical performance and variant interpretation remain relevant difficulties for its clinical implementation. Methods: We developed a novel NGS panel with 199 genes associated with non-syndromic and/or syndromic SNHL. We evaluated the analytical sensitivity and specificity of the panel on 1624 known single nucleotide variants (SNVs) and indels on a mixture of genomic DNA from 10 previously characterized lymphoblastoid cell lines, and analyzed 50 Spanish patients with presumed hereditary SNHL not caused by GJB2/GJB6, OTOF nor MT-RNR1 mutations. Results: The analytical sensitivity of the test to detect SNVs and indels on the DNA mixture from the cell lines was > 99.5%, with a specificity > 99.9%. The diagnostic yield on the SNHL patients was 42% (21/50): 47.6% (10/21) with autosomal recessive inheritance pattern (BSND, CDH23, MYO15A, STRC [n = 2], USH2A [n = 3], RDX, SLC26A4); 38.1% (8/21) autosomal dominant (ACTG1 [n = 3; 2 de novo], CHD7, GATA3 [de novo], MITF, P2RX2, SOX10), and 14.3% (3/21) X-linked (COL4A5 [de novo], POU3F4, PRPS1). 46.9% of causative variants (15/32) were not in the databases. 28.6% of genetically diagnosed cases (6/21) had previously undetected syndromes (Barakat, Usher type 2A [n = 3] and Waardenburg [n = 2]). 19% of genetic diagnoses (4/21) were attributable to large deletions/duplications (STRC deletion [n = 2]; partial CDH23 duplication; RDX exon 2 deletion). Conclusions: In the era of precision medicine, obtaining an etiologic diagnosis of SNHL is imperative. Here, we contribute to show that, with the right methodology, NGS can be transferred to the clinical practice, boosting the yield of SNHL genetic diagnosis to 50-60% (including GJB2/GJB6 alterations), improving diagnostic/prognostic accuracy, refining genetic and reproductive counseling and revealing clinically relevant undiagnosed syndromes. |
| publishDate |
2018 |
| dc.date.none.fl_str_mv |
2018 2018-07-09 2018 2018-07-09 |
| dc.type.none.fl_str_mv |
research article http://purl.org/coar/resource_type/c_2df8fbb1 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/20.500.13003/9217 |
| url |
https://hdl.handle.net/20.500.13003/9217 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ |
| eu_rights_str_mv |
openAccess |
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application/pdf |
| dc.publisher.none.fl_str_mv |
BMC |
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BMC |
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reponame:Docusalut instname:Conselleria de Salut i Consum del Govern de les Illes Balears |
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Conselleria de Salut i Consum del Govern de les Illes Balears |
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Docusalut |
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1869419620274798592 |
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15,198674 |