Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Italian Journal of Pediatrics
Published in: Italian Journal of Pediatrics 1/2017

Open Access 01-12-2017 | Review

Intersociety policy statement on the use of whole-exome sequencing in the critically ill newborn infant

Authors: Alessandro Borghesi, Maria Antonietta Mencarelli, Luigi Memo, Giovanni Battista Ferrero, Andrea Bartuli, Maurizio Genuardi, Mauro Stronati, Alberto Villani, Alessandra Renieri, Giovanni Corsello, on behalf of their respective Scientific Societies

Published in: Italian Journal of Pediatrics | Issue 1/2017

Login to get access

Abstract

The rapid advancement of next-generation sequencing (NGS) technology and the decrease in costs for whole-exome sequencing (WES) and whole-genome sequening (WGS), has prompted its clinical application in several fields of medicine. Currently, there are no specific guidelines for the use of NGS in the field of neonatal medicine and in the diagnosis of genetic diseases in critically ill newborn infants. As a consequence, NGS may be underused with reduced diagnostic success rate, or overused, with increased costs for the healthcare system. Most genetic diseases may be already expressed during the neonatal age, but their identification may be complicated by nonspecific presentation, especially in the setting of critical clinical conditions. The differential diagnosis process in the neonatal intensive care unit (NICU) may be time-consuming, uncomfortable for the patient due to repeated sampling, and ineffective in reaching a molecular diagnosis during NICU stay. Serial gene sequencing (Sanger sequencing) may be successful only for conditions for which the clinical phenotype strongly suggests a diagnostic hypothesis and for genetically homogeneous diseases. Newborn screenings with Guthrie cards, which vary from country to country, are designed to only test for a few dozen genetic diseases out of the more than 6000 diseases for which a genetic characterization is available. The use of WES in selected cases in the NICU may overcome these issues. We present an intersociety document that aims to define the best indications for the use of WES in different clinical scenarios in the NICU. We propose that WES is used in the NICU for critically ill newborn infants when an early diagnosis is desirable to guide the clinical management during NICU stay, when a strong hypothesis cannot be formulated based on the clinical phenotype or the disease is genetically heterogeneous, and when specific non-genetic laboratory tests are not available. The use of WES may reduce the time for diagnosis in infants during NICU stay and may eventually result in cost-effectiveness.
Literature
1.
Frebourg T. The challenge for the next generation of medical geneticists. Hum Mutat. 2014;35:909–11.CrossRefPubMed
2.
Tetreault M, Bareke E, Nadaf J, Alirezaie N, Majewski J. Whole-exome sequencing as a diagnostic tool: current challenges and future opportunities. Expert Rev Mol Diagn. 2015;15:749–60.PubMed
3.
4.
5.
Saunders CJ, Miller NA, Soden SE, Dinwiddie DL, Noll A, Alnadi NA, Andraws N, Patterson ML, Krivohlavek LA, Fellis J, et al. Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. Sci Transl Med. 2012;4:154ra135.CrossRefPubMedPubMedCentral
6.
7.
8.
Olshan AF, Hobbs CA, Shaw GM. Discovery of genetic susceptibility factors for human birth defects: an opportunity for a National Agenda. Am J Med Genet A. 2011;155A:1794–7.CrossRefPubMed
9.
10.
Baker K, Sanchez-de-Toledo J, Munoz R, Orr R, Kiray S, Shiderly D, Clemens M, Wearden P, Morell VO, Chrysostomou C. Critical congenital heart disease--utility of routine screening for chromosomal and other extracardiac malformations. Congenit Heart Dis. 2012;7:145–50.CrossRefPubMed
11.
Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics. 2000;105:e10.CrossRefPubMed
12.
13.
14.
15.
16.
17.
Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86:749–64.CrossRefPubMedPubMedCentral
18.
Stamouli S, Anderlid B-M, Willfors C, Thiruvahindrapuram B, Wei J, Berggren S, Nordgren A, Scherer S, Lichtenstein P, Tammimies K, Bolte S: Copy Number Variation Analysis of 100 Twin Pairs Enriched for Neurodevelopmental Disorders. bioRxiv 2017. doi:10.​1101/​152611.
19.
Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, Shendure J. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet. 2011;12:745–55.CrossRefPubMed
20.
de Ligt J, Boone PM, Pfundt R, Vissers LE, Richmond T, Geoghegan J, O'Moore K, de Leeuw N, Shaw C, Brunner HG, et al: Detection of clinically relevant copy number variants with whole-exome sequencing. Hum Mutat 2013, 34:1439-1448.
21.
22.
Vetro A, Godin D, Lesende I, Limongelli I, Ranzani GN, Novara F, Bonaglia MC, Rinaldi B, Franchi F, Manolakos E, et al. Diagnostic application of a capture based NGS test for the concurrent detection of variants in sequence and copy number as well as LOH. Clin Genet. 2017. doi:10.​1111/​cge.​13060.
23.
Choi M, Scholl UI, Ji W, Liu T, Tikhonova IR, Zumbo P, Nayir A, Bakkaloglu A, Ozen S, Sanjad S, et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A. 2009;106:19096–101.CrossRefPubMedPubMedCentral
24.
Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, et al. Exome sequencing identifies the cause of a mendelian disorder. Nat Genet. 2010;42:30–5.CrossRefPubMed
25.
Tarailo-Graovac M, Shyr C, Ross CJ, Horvath GA, Salvarinova R, Ye XC, Zhang LH, Bhavsar AP, Lee JJ, Drogemoller BI, et al. Exome sequencing and the Management of Neurometabolic Disorders. N Engl J Med. 2016;374:2246–55.CrossRefPubMedPubMedCentral
26.
Carss KJ, Hillman SC, Parthiban V, McMullan DJ, Maher ER, Kilby MD, Hurles ME. Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound. Hum Mol Genet. 2014;23:3269–77.CrossRefPubMedPubMedCentral
27.
Willig LK, Petrikin JE, Smith LD, Saunders CJ, Thiffault I, Miller NA, Soden SE, Cakici JA, Herd SM, Twist G, et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med. 2015;3:377–87.CrossRefPubMedPubMedCentral
28.
Desbats MA, Vetro A, Limongelli I, Lunardi G, Casarin A, Doimo M, Spinazzi M, Angelini C, Cenacchi G, Burlina A, et al. Primary coenzyme Q10 deficiency presenting as fatal neonatal multiorgan failure. Eur J Hum Genet. 2015;23:1254–8.CrossRefPubMedPubMedCentral
29.
Srivastava S, Cohen JS, Vernon H, Baranano K, McClellan R, Jamal L, Naidu S, Fatemi A. Clinical whole exome sequencing in child neurology practice. Ann Neurol. 2014;76:473–83.CrossRefPubMed
30.
Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, Kanapin A, Lunter G, Fiddy S, Allan C, et al. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat Genet. 2015;47:717–26.CrossRefPubMedPubMedCentral
31.
Eilbeck K, Quinlan A, Yandell M. Settling the score: variant prioritization and Mendelian disease. Nat Rev Genet. 2017;18:599–612.CrossRefPubMed
32.
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O'Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.CrossRefPubMedPubMedCentral
33.
Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, Abecasis GR, The_1000_Genomes_Project_Consortium. A global reference for human genetic variation. Nature. 2015;526:68–74.CrossRefPubMed
34.
Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, Hoover J, et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016;44:D862–8.CrossRefPubMed
35.
Ng SB, Turner EH, Robertson PD, Flygare SD, Bigham AW, Lee C, Shaffer T, Wong M, Bhattacharjee A, Eichler EE, et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature. 2009;461:272–6.CrossRefPubMedPubMedCentral
36.
37.
Belkadi A, Bolze A, Itan Y, Cobat A, Vincent QB, Antipenko A, Shang L, Boisson B, Casanova JL, Abel L. Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants. Proc Natl Acad Sci U S A. 2015;112:5473–8.CrossRefPubMedPubMedCentral
38.
39.
Hehir-Kwa JY, Claustres M, Hastings RJ, van Ravenswaaij-Arts C, Christenhusz G, Genuardi M, Melegh B, Cambon-Thomsen A, Patsalis P, Vermeesch J, et al. Towards a European consensus for reporting incidental findings during clinical NGS testing. Eur J Hum Genet. 2015;23:1601–6.CrossRefPubMedPubMedCentral
40.
Kalia SS, Adelman K, Bale SJ, Chung WK, Eng C, Evans JP, Herman GE, Hufnagel SB, Klein TE, Korf BR, et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med. 2017;19:249–55.CrossRefPubMed
41.
Ceyhan-Birsoy O, Machini K, Lebo MS, Yu TW, Agrawal PB, Parad RB, Holm IA, McGuire A, Green RC, Beggs AH, Rehm HL. A curated gene list for reporting results of newborn genomic sequencing. Genet Med. 2017;19:809–18.CrossRefPubMed
42.
43.
44.
45.
Berg JS, Agrawal PB, Bailey DB Jr, Beggs AH, Brenner SE, Brower AM, Cakici JA, Ceyhan-Birsoy O, Chan K, Chen F, et al. Newborn sequencing in genomic medicine and public health. Pediatrics. 2017;139
46.
Mollison L, Berg JS. Genetic screening: birthright or earned with age? Expert Rev Mol Diagn. 2017;17:735–8.CrossRefPubMed
Metadata
Title
Intersociety policy statement on the use of whole-exome sequencing in the critically ill newborn infant
Authors
Alessandro Borghesi
Maria Antonietta Mencarelli
Luigi Memo
Giovanni Battista Ferrero
Andrea Bartuli
Maurizio Genuardi
Mauro Stronati
Alberto Villani
Alessandra Renieri
Giovanni Corsello
on behalf of their respective Scientific Societies
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Italian Journal of Pediatrics / Issue 1/2017
Electronic ISSN: 1824-7288
DOI
https://doi.org/10.1186/s13052-017-0418-0

Other articles of this Issue 1/2017

Italian Journal of Pediatrics 1/2017 Go to the issue

Research

Percentiles of serum uric acid and cardiometabolic abnormalities in obese Italian children and adolescents

Research

Efficacy and usability of a novel nebulizer targeting both upper and lower airways

Research

Immunomodulatory constituents of human breast milk and immunity from bronchiolitis

Commentary

Novel insight into Chronic Inflammatory Demyelinating Polineuropathy in APECED syndrome: molecular mechanisms and clinical implications in children

Research

A cohort analysis of neonatal hospital mortality rate and predictors of neonatal mortality in a sub-urban hospital of Cameroon

Research

IOEASMA: an integrated clinical and educational pathway for managing asthma in children and adolescents