Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant

Almost half of all individuals affected by intellectual disability (ID) remain undiagnosed. In the Solve-RD project, exome sequencing (ES) datasets from unresolved individuals with (syndromic) ID (n = 1,472 probands) are systematically reanalyzed, starting from raw sequencing files, followed by geno...

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Autores: de Boer, Elke, Yaldiz, Burcu, Denommé-Pichon, Anne-Sophie, Matalonga, Leslie, Laurie, Steve, Solve-RD SNV-indel working group, Solve-RD-DITF-ITHACA, Cuesta de la Plaza, Isabel, Posada De la Paz, Manuel
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/15565
Acceso en línea:http://hdl.handle.net/20.500.12105/15565
Access Level:acceso abierto
Palabra clave:Adolescent
Brain
Developmental Disabilities
Face
Female
Humans
Intellectual Disability
Microcephaly
Mutation, Missense
Strabismus
Tubulin
Exome Sequencing
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oai_identifier_str oai:repisalud.isciii.es:20.500.12105/15565
network_acronym_str ES
network_name_str España
repository_id_str
spelling Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variantde Boer, ElkeYaldiz, BurcuDenommé-Pichon, Anne-SophieMatalonga, LeslieLaurie, SteveSolve-RD SNV-indel working groupSolve-RD-DITF-ITHACACuesta de la Plaza, IsabelPosada De la Paz, ManuelAdolescentBrainDevelopmental DisabilitiesFaceFemaleHumansIntellectual DisabilityMicrocephalyMutation, MissenseStrabismusTubulinExome SequencingAlmost half of all individuals affected by intellectual disability (ID) remain undiagnosed. In the Solve-RD project, exome sequencing (ES) datasets from unresolved individuals with (syndromic) ID (n = 1,472 probands) are systematically reanalyzed, starting from raw sequencing files, followed by genome-wide variant calling and new data interpretation. This strategy led to the identification of a disease-causing de novo missense variant in TUBB3 in a girl with severe developmental delay, secondary microcephaly, brain imaging abnormalities, high hypermetropia, strabismus and short stature. Interestingly, the TUBB3 variant could only be identified through reanalysis of ES data using a genome-wide variant calling approach, despite being located in protein coding sequence. More detailed analysis revealed that the position of the variant within exon 5 of TUBB3 was not targeted by the enrichment kit, although consistent high-quality coverage was obtained at this position, resulting from nearby targets that provide off-target coverage. In the initial analysis, variant calling was restricted to the exon targets ± 200 bases, allowing the variant to escape detection by the variant calling algorithm. This phenomenon may potentially occur more often, as we determined that 36 established ID genes have robust off-target coverage in coding sequence. Moreover, within these regions, for 17 genes (likely) pathogenic variants have been identified before. Therefore, this clinical report highlights that, although compute-intensive, performing genome-wide variant calling instead of target-based calling may lead to the detection of diagnostically relevant variants that would otherwise remain unnoticed.ElsevierDutch Research Council (Holanda)Unión Europea. Comisión Europea. H2020Netherlands Organisation for Health Research and Development20232023-03-0320222022-01-0120222022-01-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/15565reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengEuropean Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 779257open accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/155652026-06-12T12:43:37Z
dc.title.none.fl_str_mv Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant
title Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant
spellingShingle Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant
de Boer, Elke
Adolescent
Brain
Developmental Disabilities
Face
Female
Humans
Intellectual Disability
Microcephaly
Mutation, Missense
Strabismus
Tubulin
Exome Sequencing
title_short Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant
title_full Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant
title_fullStr Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant
title_full_unstemmed Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant
title_sort Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant
dc.creator.none.fl_str_mv de Boer, Elke
Yaldiz, Burcu
Denommé-Pichon, Anne-Sophie
Matalonga, Leslie
Laurie, Steve
Solve-RD SNV-indel working group
Solve-RD-DITF-ITHACA
Cuesta de la Plaza, Isabel
Posada De la Paz, Manuel
author de Boer, Elke
author_facet de Boer, Elke
Yaldiz, Burcu
Denommé-Pichon, Anne-Sophie
Matalonga, Leslie
Laurie, Steve
Solve-RD SNV-indel working group
Solve-RD-DITF-ITHACA
Cuesta de la Plaza, Isabel
Posada De la Paz, Manuel
author_role author
author2 Yaldiz, Burcu
Denommé-Pichon, Anne-Sophie
Matalonga, Leslie
Laurie, Steve
Solve-RD SNV-indel working group
Solve-RD-DITF-ITHACA
Cuesta de la Plaza, Isabel
Posada De la Paz, Manuel
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Dutch Research Council (Holanda)
Unión Europea. Comisión Europea. H2020
Netherlands Organisation for Health Research and Development
dc.subject.none.fl_str_mv Adolescent
Brain
Developmental Disabilities
Face
Female
Humans
Intellectual Disability
Microcephaly
Mutation, Missense
Strabismus
Tubulin
Exome Sequencing
topic Adolescent
Brain
Developmental Disabilities
Face
Female
Humans
Intellectual Disability
Microcephaly
Mutation, Missense
Strabismus
Tubulin
Exome Sequencing
description Almost half of all individuals affected by intellectual disability (ID) remain undiagnosed. In the Solve-RD project, exome sequencing (ES) datasets from unresolved individuals with (syndromic) ID (n = 1,472 probands) are systematically reanalyzed, starting from raw sequencing files, followed by genome-wide variant calling and new data interpretation. This strategy led to the identification of a disease-causing de novo missense variant in TUBB3 in a girl with severe developmental delay, secondary microcephaly, brain imaging abnormalities, high hypermetropia, strabismus and short stature. Interestingly, the TUBB3 variant could only be identified through reanalysis of ES data using a genome-wide variant calling approach, despite being located in protein coding sequence. More detailed analysis revealed that the position of the variant within exon 5 of TUBB3 was not targeted by the enrichment kit, although consistent high-quality coverage was obtained at this position, resulting from nearby targets that provide off-target coverage. In the initial analysis, variant calling was restricted to the exon targets ± 200 bases, allowing the variant to escape detection by the variant calling algorithm. This phenomenon may potentially occur more often, as we determined that 36 established ID genes have robust off-target coverage in coding sequence. Moreover, within these regions, for 17 genes (likely) pathogenic variants have been identified before. Therefore, this clinical report highlights that, although compute-intensive, performing genome-wide variant calling instead of target-based calling may lead to the detection of diagnostically relevant variants that would otherwise remain unnoticed.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022-01-01
2022
2022-01-01
2023
2023-03-03
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/15565
url http://hdl.handle.net/20.500.12105/15565
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv European Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 779257
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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