Application of exome sequencing for prenatal diagnosis: a rapid scoping review

Pratt, Misty; Garritty, Chantelle; Thuku, Micere; Esmaeilisaraji, Leila; Hamel, Candyce; Hartley, Taila; Millar, Kathryn; Skidmore, Becky; Dougan, Shelley; Armour, Christine M.

doi:10.1038/s41436-020-0918-y

Cited by 31 publications

(39 citation statements)

References 47 publications

(181 reference statements)

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“…Genomic technologies, such as next generation sequencing, enable faster diagnosis through simultaneous interrogation of a patient’s complete set of DNA (genome), protein-coding regions (exome) or multi-gene panels [ 7 , 9 ]. Adoption of genomic testing as a clinical standard of care requires evidence of clinical benefit and cost-effectiveness, the latter typically established through comparing incremental costs with quality-adjusted life years (QALYs) gained [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Toward the diagnosis of rare childhood genetic diseases: what do parents value most?

et al. 2021

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Genomic testing is becoming routine for diagnosing rare childhood genetic disease. Evidence underlying sustainable implementation is limited, focusing on short-term endpoints such as diagnostic yield, unable to fully characterize patient and family valued outcomes. Although genomic testing is becoming widely available, evidentiary and outcomes uncertainty persist as key challenges for implementation. We examine whether the current evidence base reflects public tolerance for uncertainty for genomics to diagnose rare childhood genetic disease. We conducted focus groups with general population parents in Vancouver, Canada, and Oxford, United Kingdom, to discuss expectations and concerns related to genomic testing to diagnose rare childhood genetic disease. Applying a purposive sampling technique, recruitment continued until thematic saturation was reached. Transcripts were analysed using thematic analysis. Thirty-three parents participated across four focus groups. Participants valued causal diagnoses alongside management strategies to improve patient health and wellbeing. Further, participants valued expanding the evidence base to reduce evidentiary uncertainty while ensuring security of information. Willingness to pay out of pocket for testing reflected perceived familial health benefit. Diagnostic yield fails to fully capture valued outcomes, and efforts to resolve uncertainty better reflect public priorities. Evaluations of genomic testing that fully integrate valued endpoints are necessary to ensure consistency with best practices and public willingness to accept the uncertain familial benefit.

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Section: Introductionmentioning

confidence: 99%

Toward the diagnosis of rare childhood genetic diseases: what do parents value most?

et al. 2021

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“…In comparison with the postnatal literature, there is a relative paucity of scientific literature regarding the application of GWS technologies in pregnancy. A recent scoping review found that the diagnostic yield varied dramatically between studies 8. This was attributed to significant differences in study design, particularly criteria for inclusion (eg, specific fetal findings or anomalies), timing of testing and methods for analysis 8.…”

Section: Considerationsmentioning

confidence: 99%

“…8 This was attributed to significant differences in study design, particularly criteria for inclusion (eg, specific fetal findings or anomalies), timing of testing and methods for analysis. 8 Most studies are retrospective case series of highly selected and small numbers (typically <50) of fetuses with diverse indications for testing (eg, stillbirths, fetuses from terminated pregnancies and other highly selected cases based on anomalies present), which make them difficult to compare and generalise with regard to the diagnostic utility of this testing. Two large prospective studies using a trio ES approach have been published that recruited singleton pregnancies with structural anomalies, including increased nuchal translucency, identified on prenatal ultrasound.…”

Section: Considerations Diagnostic Yield Of Fetal Gws During Pregnancymentioning

confidence: 99%

Clinical application of fetal genome-wide sequencing during pregnancy: position statement of the Canadian College of Medical Geneticists

et al. 2021

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Purpose and scopeThe aim of this position statement is to provide recommendations for Canadian healthcare professionals regarding the use of genome-wide sequencing (GWS) in the context of diagnostic testing of the fetus during pregnancy. This statement was developed to facilitate clinical translation of GWS as a prenatal diagnostic test and the development of best practices in Canada, but the applicability of this document is broader and aims to help professionals in other healthcare systems.Methods of statement developmentA multidisciplinary group was assembled to review existing literature on fetal GWS for genetic diagnosis in the context of suspected monogenic diseases and to make recommendations relevant to the Canadian context. The statement was circulated for comments to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors on 19 February 2021.Results and conclusionsThe use of prenatal GWS is indicated for the investigation of multiple fetal anomalies. Its use in the context of isolated fetal anomaly should be guided by available resources and current evidence, which is continually changing. During pregnancy, GWS should be ordered by, or in collaboration with, a medical geneticist. It should be used following detailed phenotyping to interrogate known disease genes, preferably using a trio approach, following detailed fetal phenotyping. Testing should be done with an overall aim to help in the management of the pregnancy, delivery and postnatal care. It should be guided by personal utility of the test for the pregnant person and clinical utility for pregnancy and birth management, as outlined herein. Genetic counselling is crucial in making the parental decision an informed decision. Chromosomal microarray analysis should be completed in parallel or prior to GWS and should be preceded by Quantitative Fluorescent PCR (QF-PCR) for detection of common aneuploidies. In normal circumstances, only pathogenic and likely pathogenic variants with a high likelihood of being associated with the identified fetal anomalies should be reported. Reporting of secondary findings, defined as purposeful analysis of variants in a set of medically actionable genes, should not, by default, be performed in the prenatal context. Laboratories should only report incidental findings that reveal risk of a significant Mendelian condition during infancy and childhood. Should a laboratory have a policy for reporting incidental findings in medically actionable adult-onset conditions, they should only be reported with explicit opt-in consent signed by the tested individuals. Genetic counselling is crucial in disclosing the test results and the implications the results may have for the fetus. It should be emphasised that negative results do not rule out a genetic diagnosis nor guarantee a good prognosis. Postnatal phenotyping and reanalysis of existing data should be considered. Families should be given the opportunity to participate in research studies as appropriate. These recommendations will be routinely re-evaluated as knowledge of the diagnostic and clinical utility of fetal GWS during pregnancy improves.

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“…Probably, there will be many other genes implicated in this group of diseases and, as genetic testing becomes more widely adopted in the clinic, a greater proportion of all individuals with urinary tract malformations will be found to have a genetic cause. While most genetic diagnoses are currently made in babies and older children, prenatal genetic testing with exome sequencing is feasible [27]. The latter may become more widely adopted, especially by families who already have a child with a genetically defined urinary tract malformation, and even more so if specific treatments were to become available.…”

Section: Clinical Impact Of Urinary Tract Malformationsmentioning

confidence: 99%

Envisioning treating genetically-defined urinary tract malformations with viral vector-mediated gene therapy

Lopes

Woolf

Roberts

2021

Journal of Pediatric Urology

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Application of exome sequencing for prenatal diagnosis: a rapid scoping review

Cited by 31 publications

References 47 publications

Toward the diagnosis of rare childhood genetic diseases: what do parents value most?

Toward the diagnosis of rare childhood genetic diseases: what do parents value most?

Clinical application of fetal genome-wide sequencing during pregnancy: position statement of the Canadian College of Medical Geneticists

Envisioning treating genetically-defined urinary tract malformations with viral vector-mediated gene therapy

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