Whole-genome sequencing expands diagnostic utility and improves clinical management in paediatric medicine
The standard of care for first-tier clinical investigation of the aetiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy-number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion–deletions...
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Published in | Npj genomic medicine Vol. 1; no. 1; p. 15012 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
13.01.2016
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
ISSN | 2056-7944 2056-7944 |
DOI | 10.1038/npjgenmed.2015.12 |
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Summary: | The standard of care for first-tier clinical investigation of the aetiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy-number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion–deletions (indels) and single-nucleotide variant (SNV) mutations. Whole-genome sequencing (WGS) has the potential to capture all classes of genetic variation in one experiment; however, the diagnostic yield for mutation detection of WGS compared to CMA, and other tests, needs to be established. In a prospective study we utilised WGS and comprehensive medical annotation to assess 100 patients referred to a paediatric genetics service and compared the diagnostic yield versus standard genetic testing. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a fourfold increase in diagnostic rate over CMA (8%
; P
value=1.42E−05) alone and more than twofold increase in CMA plus targeted gene sequencing (13%;
P
value=0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harbouring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counselling. Clinical implementation of WGS as a primary test will provide a higher diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic diagnosis.
Pediatric medicine: Diagnostic yield greatest with whole genome sequencing
Children with genetic disorders receive a diagnosis more often with full genome sequencing than with the current standard of care. A team led by Christian Marshall from the Hospital for Sick Children in Toronto, Canada, compared the diagnostic utility of sequencing the entire genome with older technologies that first look for chromosome-level abnormalities and then sometimes involve sequencing specific genes. They considered 100 children with congenital malformations or neurodevelopmental disorders. Whole genome sequencing offered a diagnosis in 34% of cases, whereas chromosome analysis yielded a diagnosis only 8% or 13% of the time, depending on whether it was followed by targeted gene sequencing. Notably, chromosome analysis never offered a diagnosis that wasn't also revealed by full genome sequencing. The authors conclude that whole genome analysis should become standard in pediatric genetics services. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 content type line 14 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work. CRM, DJS, MSM, PNR designed the study, with contributions from SB, RDC and SWS. CRM and DJS drafted the manuscript. MSM, RJ, RDC, PNR, SWS contributed to preparation of the manuscript. CRM, DJS, RJ, MSM, SB, NM were responsible for variant classification and interpretation. DM, CRM, DJS, RKCY created and developed the variant analysis pipeline. NM and CC were responsible for study coordination. BT, TN, GP, BF, BA contributed to sequence data analysis. MS, RZS, MSM were responsible for consent design, with contributions from SB, RH and CS. RH contributed to test costing and data collection. MB and MG contributed to phenotype data collection and analysis. RE, RAL, RK provided whole-genome sequencing and analysis. MSM, SB, RJ, NM, RDC, SA, RBH, RBP, MTC, LC, AC, DC, SJD, CC, LD, RE, LF, AG, BH, MH, SH, MIF, PK, NK, RK, JK, EL, HM, SMM, RML, EN, GN, NP, NQ, JR, MR, AS, AS, CS, PS, KS, RW, GY were responsible for patient recruitment, clinical phenotyping and participation in clinical review meetings. CRM and DJS had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. |
ISSN: | 2056-7944 2056-7944 |
DOI: | 10.1038/npjgenmed.2015.12 |