Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit

Daoud, Hussein; Luco, Stephanie M.; Li, Rui; Bareke, Eric; Beaulieu, Chandree L.; Jarinova, Olga; Carson, Nancy; Nikkel, Sarah M.; Graham, Gail E.; Richer, Julie; Armour, Christine M.; Bulman, Dennis E.; Chakraborty, Pranesh; Geraghty, Michael T.; Lines, Matthew A.; Lacaze‐Masmonteil, Thierry; Majewski, Jacek; Boycott, Kym M.; Dyment, David A.

doi:10.1503/cmaj.150823

Cited by 86 publications

(93 citation statements)

References 15 publications

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“…Thus far, reports show that genome sequencing of this carefully selected clinical population identifies variants that are plausibly associated with some or all of the babies’ symptoms, leading to “molecular diagnoses,” in approximately 40%−60% of cases. 13, 35, 36 Yet the clinical significance of these molecular diagnoses—their impact on the medical care of sick infants—has unfortunately only rarely mirrored the case reported by Worthey and colleagues. In that case, the diagnosis triggered a treatment that cured the child’s disease.…”

Section: Sequencing To Diagnose Sick Newborns Can Benefit Children Anmentioning

confidence: 99%

Sequencing Newborns:A Call for Nuanced Use of Genomic Technologies

Johnston¹,

Lantos²,

Goldenberg³

et al. 2018

Hastings Center Report

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Many scientists and doctors hope that affordable genome sequencing will lead to more personalized medical care and improve public health in ways that will benefit children, families, and society more broadly. One hope in particular is that all newborns could be sequenced at birth, thereby setting the stage for a lifetime of medical care and self-directed preventive actions tailored to each child's genome. Indeed, commentators often suggest that universal genome sequencing is inevitable. Such optimism can come with the presumption that discussing the potential limits, cost, and downsides of widespread application of genomic technologies is pointless, excessively pessimistic, or overly cautious. We disagree. Given the pragmatic challenges associated with determining what sequencing data mean for the health of individuals, the economic costs associated with interpreting and acting on such data, and the psychosocial costs of predicting one's own or one's child's future life plans based on uncertain testing results, we think this hope and optimism deserve to be tempered. In the analysis that follows, we distinguish between two reasons for using sequencing: to diagnose individual infants who have been identified as sick and to screen populations of infants who appear to be healthy. We also distinguish among three contexts in which sequencing for either diagnosis or screening could be deployed: in clinical medicine, in public health programs, and as a direct-to-consumer service. Each of these contexts comes with different professional norms, policy considerations, and public expectations. Finally, we distinguish between two main types of genome sequencing: targeted sequencing, where only specific genes are sequenced or analyzed, and whole-exome or whole-genome sequencing, where all the DNA or all the coding segments of all genes are sequenced and analyzed. In a symptomatic newborn, targeted or genome-wide sequencing can help guide other tests for diagnosis or for specific treatment that is urgently needed. Clinicians use the infant's symptoms (or phenotype) to interrogate the sequencing data. These same complexities and uncertainties, however, limit the usefulness of genome-wide sequencing as a population screening tool. While we recognize considerable benefit in using targeted sequencing to screen for or detect specific conditions that meet the criteria for inclusion in newborn screening panels, use of genome-wide sequencing as a sole screening tool for newborns is at best premature. We conclude that sequencing technology can be beneficially used in newborns when that use is nuanced and attentive to context.

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Section: Sequencing To Diagnose Sick Newborns Can Benefit Children Anmentioning

confidence: 99%

Sequencing Newborns:A Call for Nuanced Use of Genomic Technologies

Johnston¹,

Lantos²,

Goldenberg³

et al. 2018

Hastings Center Report

View full text Add to dashboard Cite

show abstract

“…However, WES/WGS may still take weeks to months, pose logistical hurdles, and there may be restrictions with regards to the allocation of locally available resources. For example, one center with extensive resources is able to offer WGS and analysis within a 48‐hour period to diagnose newborns with rare disease including encephalopathy, whereas other centers, with less access to high‐throughput sequencing, may be limited to comprehensive panel testing and take several months to receive results . There is a risk of incidental and secondary findings for genomic sequencing, and a thorough pre‐test counseling on these issues can be a challenge in the setting of the neonatal intensive care unit for those with EIEE.…”

Section: Genetic Causes Of Specific Epilepsy Phenotypes and Syndromementioning

confidence: 99%

Epilepsy genetics: Current knowledge, applications, and future directions

2018

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The rapid pace of disease gene discovery has resulted in tremendous advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, and genomes are now available and have led to higher diagnostic rates and insights into the underlying disease processes. As such, the contribution to the care of patients by medical geneticists, neurogeneticists and genetic counselors are significant; the dysmorphic examination, the necessary pre- and post-test counseling, the selection of the appropriate next-generation sequencing-based test(s), and the interpretation of sequencing results require a care provider to have a comprehensive working knowledge of the strengths and limitations of the available testing technologies. As the underlying mechanisms of the encephalopathies and epilepsies are better understood, there may be opportunities for the development of novel therapies based on an individual's own specific genotype. Drug screening with in vitro and in vivo models of epilepsy can potentially facilitate new treatment strategies. The future of epilepsy genetics will also probably include other-omic approaches such as transcriptomes, metabolomes, and the expanded use of whole genome sequencing to further improve our understanding of epilepsy and provide better care for those with the disease.

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“…7,10 The need for a rapid comprehensive genetic diagnosis in ICUs for critically ill babies, especially those in level III and IV NICUs is paramount for both prognostication and clinical decision-making. 8,16 …”

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confidence: 99%

Use of Exome Sequencing for Infants in Intensive Care Units

et al. 2017

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Importance: While congenital malformations and genetic diseases are a leading cause of early infant death, the contribution of single-gene disorders in this group is undetermined. Objective: To determine the diagnostic yield and utility of clinical exome sequencing in critically ill infants. Design, setting, participants: Clinical exome sequencing was performed on 278 unrelated infants within the first 100 days of life, admitted to Texas Children’s Hospital in Houston, over a period of five years, between December 2011 and January 2017. Exome sequencing types included proband exome, trio exome, and critical trio exome, a rapid genomic assay for seriously-ill infants. Main outcomes and measures: Indications for testing, diagnostic yield of clinical exome sequencing, turnaround time, molecular findings, patient age at diagnosis, and impact on medical management in a group of critically ill infants suspected to have genetic disorders. Results: Clinical indications for exome sequencing included a wide range of medical concerns. Overall, molecular diagnosis was achieved in 102/278 infants by clinical exome sequencing with a diagnostic yield of 36.7%. The diagnosis affected medical management in 53/102 (52.0%) of infants, with substantial impact on informed redirection of care, initiation of new subspecialist care, medication/dietary modifications, and furthering life-saving procedures in select patients. Critical trio exome revealed a molecular diagnosis in 32/63 infants (50.8%) at 33.1±5.6 days of life with turnaround time (TAT) of 13.0 ± 0.4 days. Clinical care was altered by the diagnosis in 23/32 (71.9%) patients. The diagnostic yield, patient age at diagnosis, and medical impact in the group that underwent critical trio exome is significantly different comparing to regular exome testing. For deceased infants (n=81), genetic disorders were molecular diagnosed in 39 (48.1%) by exome sequencing with implications for recurrence risk counseling. Conclusions and relevance: Exome sequencing is a powerful tool for the diagnostic evaluation of critically ill infants with suspected monogenic disorders in the neonatal and pediatric ICUs, leading to notable impact on clinical decision-making.

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Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit

Cited by 86 publications

References 15 publications

Sequencing Newborns:A Call for Nuanced Use of Genomic Technologies

Sequencing Newborns:A Call for Nuanced Use of Genomic Technologies

Epilepsy genetics: Current knowledge, applications, and future directions

Use of Exome Sequencing for Infants in Intensive Care Units

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