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Refinements and considerations for trio whole-genome sequence analysis when investigating Mendelian diseases presenting in early childhood.

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cam.issuedOnline2022-04-25
cam.orpheus.success2022-08-04
dc.contributor.authorFrench, Courtney E
dc.contributor.authorDolling, Helen
dc.contributor.authorMégy, Karyn
dc.contributor.authorSanchis-Juan, Alba
dc.contributor.authorKumar, Ajay
dc.contributor.authorDelon, Isabelle
dc.contributor.authorWakeling, Matthew
dc.contributor.authorMallin, Lucy
dc.contributor.authorAgrawal, Shruti
dc.contributor.authorAustin, Topun
dc.contributor.authorWalston, Florence
dc.contributor.authorPark, Soo-Mi
dc.contributor.authorParker, Alasdair
dc.contributor.authorPiyasena, Chinthika
dc.contributor.authorBradbury, Kimberley
dc.contributor.authorNext Generation Children’s Project Consortium
dc.contributor.authorEllard, Sian
dc.contributor.authorRowitch, David H
dc.contributor.authorRaymond, F Lucy
dc.contributor.orcidRowitch, David [0000-0002-0079-0060]
dc.date.accessioned2022-06-19T02:31:52Z
dc.date.available2022-06-19T02:31:52Z
dc.date.issued2022-07-14
dc.date.updated2022-06-19T02:31:49Z
dc.description.abstractTo facilitate early deployment of whole-genome sequencing (WGS) for severely ill children, a standardized pipeline for WGS analysis with timely turnaround and primary care pediatric uptake is needed. We developed a bioinformatics pipeline for comprehensive gene-agnostic trio WGS analysis of children suspected of having an undiagnosed monogenic disease that included detection and interpretation of primary genetic mechanisms of disease, including SNVs/indels, CNVs/SVs, uniparental disomy (UPD), imprinted genes, short tandem repeat expansions, mobile element insertions, SMN1/2 copy number calling, and mitochondrial genome variants. We assessed primary care practitioner experience and competence in a large cohort of 521 families (comprising 90% WGS trios). Children were identified by primary practitioners for recruitment, and we used the UK index of multiple deprivation to confirm lack of patient socio-economic status ascertainment bias. Of the 521 children sequenced, 176 (34%) received molecular diagnoses, with rates as high as 45% for neurology clinics. Twenty-three of the diagnosed cases (13%) required bespoke methods beyond routine SNV/CNV analysis. In our multidisciplinary clinician user experience assessment, both pediatricians and clinical geneticists expressed strong support for rapid WGS early in the care pathway, but requested further training in determining patient selection, consenting, and variant interpretation. Rapid trio WGS provides an efficacious single-pass screening test for children when deployed by primary practitioners in clinical settings that carry high a priori risk for rare pediatric disease presentations.
dc.identifier.doi10.17863/CAM.85644
dc.identifier.eissn2666-2477
dc.identifier.issn2666-2477
dc.identifier.other35586607
dc.identifier.otherPMC9108978
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338232
dc.languageeng
dc.language.isoeng
dc.publisherElsevier BV
dc.publisher.urlhttp://dx.doi.org/10.1016/j.xhgg.2022.100113
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceessn: 2666-2477
dc.sourcenlmid: 101772885
dc.subjectgenomics
dc.subjectmendelian disorders
dc.subjectpaediatrics
dc.subjectrapid diagnostic whole genome
dc.subjectrare disease
dc.titleRefinements and considerations for trio whole-genome sequence analysis when investigating Mendelian diseases presenting in early childhood.
dc.typeArticle
dcterms.dateAccepted2022-04-19
prism.issueIdentifier3
prism.publicationNameHGG Adv
prism.volume3
pubs.funder-project-idNational Institute for Health and Care Research (IS-BRC-1215-20014)
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1016/j.xhgg.2022.100113

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