Whole genome sequencing reveals that genetic conditions are frequent in intensively ill children

被引：202

作者：

French, Courtney E. ^{[1
]}

Delon, Isabelle ^{[2
]}

Dolling, Helen ^{[1
]}

Sanchis-Juan, Alba ^{[1
]}

Shamardina, Olga ^{[1
]}

Megy, Karyn ^{[1
]}

Abbs, Stephen ^{[2
]}

Austin, Topun ^{[2
]}

Bowdin, Sarah ^{[2
]}

Branco, Ricardo G. ^{[1
,2
,3
]}

Firth, Helen ^{[2
]}

Rowitch, David H. ^{[1
]}

Raymond, F. Lucy ^{[1
,2
,11
]}

Tuna, Salih ^{[1
]}

Aitman, Timothy J. ^{[4
]}

Ashford, Sofie ^{[1
]}

Astle, Willian J. ^{[1
]}

Bennet, David L. ^{[5
]}

Bleda, Marta ^{[1
]}

Carss, Keren J. ^{[1
]}

Chinnery, Patrick F. ^{[1
,11
]}

Deevi, Sri V. V. ^{[1
]}

Fletcher, Debra ^{[1
]}

Gale, Daniel P. ^{[6
]}

Graf, Stefan F. ^{[1
]}

Hu, Fengyuan ^{[1
]}

James, Roger ^{[1
]}

Kasanicki, Mary A. ^{[1
,11
]}

Kingston, Nathalie ^{[1
]}

Koziell, Ania B. ^{[7
]}

Allen, Hana Lango ^{[1
]}

Maher, Eamonn R. ^{[1
,11
]}

Markus, Hugh S. ^{[1
,11
]}

Meacham, Stuart ^{[1
]}

Morrell, Nicholas W. ^{[1
,11
]}

Penkett, Christopher J. ^{[1
]}

Roberts, Irene ^{[8
]}

Sanchis-Juan, Alba ^{[1
]}

Smith, Kenneth G. C. ^{[1
,11
]}

Stark, Hannah ^{[1
]}

Stirrups, Kathleen E. ^{[1
]}

Turro, Ernest ^{[1
]}

Watkins, Hugh ^{[9
]}

Williamson, Catherine ^{[10
]}

Young, Timothy ^{[1
]}

Bradley, John R. ^{[1
,11
]}

Ouwehand, Willem H. ^{[1
]}

Raymond, F. Lucy ^{[1
,2
,11
]}

Agrawal, Shruti ^{[12
]}

Armstrong, Ruth ^{[12
]}

机构：

[1] Univ Cambridge, Sch Clin Med, Cambridge Biomed Campus, Cambridge CB2 0SP, England

[2] Cambridge Univ Hosp NHS Fdn Trust, Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0QQ, England

[3] Sidra Med, Doha, Qatar

[4] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[5] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Oxford, England

[6] UCL, UCL Ctr Nephrol, London, England

[7] Kings Coll London, Dept Expt Immunobiol, London, England

[8] Univ Oxford, MRC Weatherall Inst Mol Med, MRC Mol Haematol Unit, Oxford, England

[9] Univ Oxford, Radcliffe Dept Med, Dept Cardiovasc Med, Oxford, England

[10] Kings Coll London, Div Womens Hlth, London, England

[11] Cambridge Univ Hosp NHS Fdn Trust, Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0QQ, England

[12] Cambridge Univ Hosp NHS Fdn Trust, Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0QQ, England

来源：

INTENSIVE CARE MEDICINE | 2019年 / 45卷 / 05期

关键词：

Whole genome sequencing; Genetics; Genomics; Critically ill children; NICU; PICU;

D O I：

10.1007/s00134-019-05552-x

中图分类号：

R4 [临床医学];

学科分类号：

1002 ; 100602 ;

摘要：

PurposeWith growing evidence that rare single gene disorders present in the neonatal period, there is a need for rapid, systematic, and comprehensive genomic diagnoses in ICUs to assist acute and long-term clinical decisions. This study aimed to identify genetic conditions in neonatal (NICU) and paediatric (PICU) intensive care populations.MethodsWe performed trio whole genome sequence (WGS) analysis on a prospective cohort of families recruited in NICU and PICU at a single site in the UK. We developed a research pipeline in collaboration with the National Health Service to deliver validated pertinent pathogenic findings within 2-3weeks of recruitment.ResultsA total of 195 families had whole genome analysis performed (567 samples) and 21% received a molecular diagnosis for the underlying genetic condition in the child. The phenotypic description of the child was a poor predictor of the gene identified in 90% of cases, arguing for gene agnostic testing in NICU/PICU. The diagnosis affected clinical management in more than 65% of cases (83% in neonates) including modification of treatments and care pathways and/or informing palliative care decisions. A 2-3week turnaround was sufficient to impact most clinical decision-making.ConclusionsThe use of WGS in intensively ill children is acceptable and trio analysis facilitates diagnoses. A gene agnostic approach was effective in identifying an underlying genetic condition, with phenotypes and symptomatology being primarily used for data interpretation rather than gene selection. WGS analysis has the potential to be a first-line diagnostic tool for a subset of intensively ill children.

引用

页码：627 / 636

页数：10

共 31 条

[1] Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency [J].

Alston, Charlotte L. ;

Heidler, Juliana ;

Dibley, Marris G. ;

Kremer, Laura S. ;

Taylor, Lucie S. ;

Fratter, Carl ;

French, Courtney E. ;

Glasgow, Ruth I. C. ;

Feichtinger, Rene G. ;

Delon, Isabelle ;

Pagnamenta, Alistair T. ;

Dolling, Helen ;

Lemonde, Hugh ;

Aiton, Neil ;

Bjornstad, Alf ;

Henneke, Lisa ;

Gaertner, Jutta ;

Thiele, Holger ;

Tauchmannova, Katerina ;

Quaghebeur, Gerardine ;

Houstek, Josef ;

Sperl, Wolfgang ;

Raymond, F. Lucy ;

Prokisch, Holger ;

Mayr, Johannes A. ;

McFarland, Robert ;

Poulton, Joanna ;

Ryan, Michael T. ;

Wittig, Ilka ;

Henneke, Marco ;

Taylor, Robert W. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2018, 103 (04) :592-601

[2]

[Anonymous], WHOL GEN SEQ BAB

[3] Newborn Sequencing in Genomic Medicine and Public Health [J].

Berg, Jonathan S. ;

Agrawal, Pankaj B. ;

Bailey, Donald B., Jr. ;

Beggs, Alan H. ;

Brenner, Steven E. ;

Brower, Amy M. ;

Cakici, Julie A. ;

Ceyhan-Birsoy, Ozge ;

Chan, Kee ;

Chen, Flavia ;

Currier, Robert J. ;

Dukhovny, Dmitry ;

Green, Robert C. ;

Harris-Wai, Julie ;

Holm, Ingrid A. ;

Iglesias, Brenda ;

Joseph, Galen ;

Kingsmore, Stephen F. ;

Koenig, Barbara A. ;

Kwok, Pui-Yan ;

Lantos, John ;

Leeder, Steven J. ;

Lewis, Megan A. ;

McGuire, Amy L. ;

Milko, Laura V. ;

Mooney, Sean D. ;

Parad, Richard B. ;

Pereira, Stacey ;

Petrikin, Joshua ;

Powell, Bradford C. ;

Powell, Cynthia M. ;

Puck, Jennifer M. ;

Rehm, Heidi L. ;

Risch, Neil ;

Roche, Myra ;

Shieh, Joseph T. ;

Veeraraghavan, Narayanan ;

Watson, Michael S. ;

Willig, Laurel ;

Yu, Timothy W. ;

Urv, Tiina ;

Wise, Anastasia L. .

PEDIATRICS, 2017, 139 (02)

[4]

Braverman Genna, 2018, Mayo Clin Proc Innov Qual Outcomes, V2, P81, DOI 10.1016/j.mayocpiqo.2018.03.005

[5] MToolBox: a highly automated pipeline for heteroplasmy annotation and prioritization analysis of human mitochondrial variants in high-throughput sequencing [J].

Calabrese, Claudia ;

Simone, Domenico ;

Diroma, Maria Angela ;

Santorsola, Mariangela ;

Gutta, Cristiano ;

Gasparre, Giuseppe ;

Picardi, Ernesto ;

Pesole, Graziano ;

Attimonelli, Marcella .

BIOINFORMATICS, 2014, 30 (21) :3115-3117

[6] Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease [J].

Carss, Keren J. ;

Arno, Gavin ;

Erwood, Marie ;

Stephens, Jonathan ;

Sanchis-Juan, Alba ;

Hull, Sarah ;

Megy, Karyn ;

Grozeva, Detelina ;

Dewhurst, Eleanor ;

Malka, Samantha ;

Plagnol, Vincent ;

Penkett, Christopher ;

Stirrups, Kathleen ;

Rizzo, Roberta ;

Wright, Genevieve ;

Josifova, Dragana ;

Bitner-Glindzicz, Maria ;

Scott, Richard H. ;

Clement, Emma ;

Allen, Louise ;

Armstrong, Ruth ;

Brady, Angela F. ;

Carmichael, Jenny ;

Chitre, Manali ;

Henderson, Robert H. H. ;

Hurst, Jane ;

MacLaren, Robert E. ;

Murphy, Elaine ;

Paterson, Joan ;

Rosser, Elisabeth ;

Thompson, Dorothy A. ;

Wakeling, Emma ;

Ouwehand, Willem H. ;

Michaelides, Michel ;

Moore, Anthony T. ;

Webster, Andrew R. ;

Raymond, F. Lucy .

AMERICAN JOURNAL OF HUMAN GENETICS, 2017, 100 (01) :75-90

[7] Anticipating uncertainty and irrevocable decisions: provider perspectives on implementing whole-genome sequencing in critically ill children with heart disease [J].

Char, Danton S. ;

Lee, Sandra Soo-Jin ;

Magnus, David ;

Cho, Mildred .

GENETICS IN MEDICINE, 2018, 20 (11) :1455-1461

[8] Detection of long repeat expansions from PCR-free whole-genome sequence data [J].

Dolzhenko, Egor ;

van Vugt, Joke J. F. A. ;

Shaw, Richard J. ;

Bekritsky, Mitchell A. ;

van Blitterswijk, Marka ;

Narzisi, Giuseppe ;

Ajay, Subramanian S. ;

Rajan, Vani ;

Lajoie, Bryan R. ;

Johnson, Nathan H. ;

Kingsbury, Zoya ;

Humphray, Sean J. ;

Schellevis, Raymond D. ;

Brands, William J. ;

Baker, Matt ;

Rademakers, Rosa ;

Kooyman, Maarten ;

Tazelaar, Gijs H. P. ;

van Es, Michael A. ;

McLaughlin, Russell ;

Sproviero, William ;

Shatunov, Aleksey ;

Jones, Ashley ;

Al Khleifat, Ahmad ;

Pittman, Alan ;

Morgan, Sarah ;

Hardiman, Orla ;

Al-Chalabi, Ammar ;

Shaw, Chris ;

Smith, Bradley ;

Neo, Edmund J. ;

Morrison, Karen ;

Shaw, Pamela J. ;

Reeves, Catherine ;

Winterkorn, Lara ;

Wexler, Nancy S. ;

Housman, David E. ;

Ng, Christopher W. ;

Li, Alina L. ;

Taft, Ryan J. ;

van den Berg, Leonard H. ;

Bentley, David R. ;

Veldink, Jan H. ;

Eberle, Michael A. .

GENOME RESEARCH, 2017, 27 (11) :1895-1903

[9] Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization [J].

Farnaes, Lauge ;

Hildreth, Amber ;

Sweeney, Nathaly M. ;

Clark, Michelle M. ;

Chowdhury, Shimul ;

Nahas, Shareef ;

Cakici, Julie A. ;

Benson, Wendy ;

Kaplan, Robert H. ;

Kronick, Richard ;

Bainbridge, Matthew N. ;

Friedman, Jennifer ;

Gold, Jeffrey J. ;

Ding, Yan ;

Veeraraghavan, Narayanan ;

Dimmock, David ;

Kingsmore, Stephen F. .

NPJ GENOMIC MEDICINE, 2018, 3

[10] ontologyX: a suite of R packages for working with ontological data [J].

Greene, Daniel ;

Richardson, Sylvia ;

Turro, Ernest .

BIOINFORMATICS, 2017, 33 (07) :1104-1106

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