Expanding non‐invasive prenatal testing beyond chromosomes 21, 18, 13, X and Y

Benn, Peter

doi:10.1111/cge.12818

Cited by 51 publications

(55 citation statements)

References 81 publications

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“…As a result, a number of low-hanging fruits of NGS are already regularly collected and used [24], resulting increasingly in actionable therapeutic insights. After the widespread implementation of genetic diagnoses for Mendelian diseases, NGS of circulating fetal- or tumor-derived cell-free plasma DNA are prominent and successful examples of non-invasive diagnostic applications that are being used, respectively, for prenatal diagnosis of fetal aneuploidies (for example, [25, 26]) or cancer diagnosis (for example, [27–29]). Similarly, NGS of cancer cells or tumors can suggest potential therapeutic leads (for example, [30–35]).…”

Section: Big Data and Clinically Useful Knowledgementioning

confidence: 99%

Reconciling evidence-based medicine and precision medicine in the era of big data: challenges and opportunities

2016

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This era of groundbreaking scientific developments in high-resolution, high-throughput technologies is allowing the cost-effective collection and analysis of huge, disparate datasets on individual health. Proper data mining and translation of the vast datasets into clinically actionable knowledge will require the application of clinical bioinformatics. These developments have triggered multiple national initiatives in precision medicine—a data-driven approach centering on the individual. However, clinical implementation of precision medicine poses numerous challenges. Foremost, precision medicine needs to be contrasted with the powerful and widely used practice of evidence-based medicine, which is informed by meta-analyses or group-centered studies from which mean recommendations are derived. This “one size fits all” approach can provide inadequate solutions for outliers. Such outliers, which are far from an oddity as all of us fall into this category for some traits, can be better managed using precision medicine. Here, we argue that it is necessary and possible to bridge between precision medicine and evidence-based medicine. This will require worldwide and responsible data sharing, as well as regularly updated training programs. We also discuss the challenges and opportunities for achieving clinical utility in precision medicine. We project that, through collection, analyses and sharing of standardized medically relevant data globally, evidence-based precision medicine will shift progressively from therapy to prevention, thus leading eventually to improved, clinician-to-patient communication, citizen-centered healthcare and sustained well-being.

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Section: Big Data and Clinically Useful Knowledgementioning

confidence: 99%

Reconciling evidence-based medicine and precision medicine in the era of big data: challenges and opportunities

2016

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“…The expectation is that the frequency of VUS will decrease and the helpfulness of pathogenic CNV diagnoses will improve as more data accrue. The escalating uptake of methods that facilitate prenatal detection of CNV, including non-invasive prenatal testing that now permits screening for selected recurrent microdeletions, 110 will further stoke demands for reliable prognostication and genetic counselling.…”

Section: Future Considerationsmentioning

confidence: 99%

The importance of copy number variation in congenital heart disease

Costain

Silversides

2016

npj Genomic Med

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Congenital heart disease (CHD) is the most common class of major malformations in humans. The historical association with large chromosomal abnormalities foreshadowed the role of submicroscopic rare copy number variations (CNVs) as important genetic causes of CHD. Recent studies have provided robust evidence for these structural variants as genome-wide contributors to all forms of CHD, including CHD that appears isolated without extra-cardiac features. Overall, a CNV-related molecular diagnosis can be made in up to one in eight patients with CHD. These include de novo and inherited variants at established (chromosome 22q11.2), emerging (chromosome 1q21.1), and novel loci across the genome. Variable expression of rare CNVs provides support for the notion of a genetic spectrum of CHD that crosses traditional anatomic classification boundaries. Clinical genetic testing using genome-wide technologies (e.g., chromosomal microarray analysis) is increasingly employed in prenatal, paediatric and adult settings. CNV discoveries in CHD have translated to changes to clinical management, prognostication and genetic counselling. The convergence of findings at individual gene and at pathway levels is shedding light on the mechanisms that govern human cardiac morphogenesis. These clinical and research advances are helping to inform whole-genome sequencing, the next logical step in delineating the genetic architecture of CHD.

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“…Professional guidelines emphasize the importance of confirming positive screening results [22] and the PPV in a clinical cohort can be evaluated from the screen-positive cases with this outcome information. PPV is prevalence dependent and some standardization to a population incidence may be required [23]. In this study, the frequency of trisomy 21 was approximately 1.4%, which was somewhat higher than the approximately 1% that would be expected based solely on maternal age (mean 36.6 years) and gestational age (mean 13.5 weeks) [24,25].…”

Section: Discussionmentioning

confidence: 53%

A National Referral Laboratory’s Experience with the Implementation of SNP-Based Non-invasive Prenatal Screening for Fetal Aneuploidy and Select Microdeletion Syndromes

Santamaría¹,

Bermejo²,

Cigarrán³

et al. 2018

Journal of Fetal Medicine

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To retrospectively evaluate the successful test rate and performance of non-invasive prenatal screening (NIPS) for aneuploidies and microdeletions with international transportation of samples. Blood samples from Iberian women with singleton pregnancies were sent to a US laboratory for NIPS for aneuploidy and microdeletion syndromes (22q11.2, 1p36, Cri-du-chat, Prader Willi and Angelman). The NIPS methodology involved the analysis of single nucleotide polymorphisms in cell-free DNA in maternal plasma. Women with high-risk results were offered karyotyping and/or microarray confirmatory studies. Based on 14,175 women with successful testing (98.76% of all referrals), the overall test positive rate was 2.37% (1.9% for aneuploidy and 0.47% for microdeletion syndromes). Based on cases with known outcome, the positive predictive values (PPVs) were: for trisomy 21, 98.6%; trisomy 18, 85.7%; trisomy 13, 71.4%; monosomy-X, 87.5%; other sex chromosome aneuploidies, 100%; 22q11.2 deletion, 15.4%; and other microdeletions combined, 20%. With a protocol change that involved selective use of resequencing at a higher depth of read, the PPV for 22q11.2 deletion increased to 33.3 and 75% for the other microdeletions. Effective NIPS for both aneuploidies and select microdeletion syndromes can be provided even when this involves international transportation of blood specimens.

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Expanding non‐invasive prenatal testing beyond chromosomes 21, 18, 13, X and Y

Cited by 51 publications

References 81 publications

Reconciling evidence-based medicine and precision medicine in the era of big data: challenges and opportunities

Reconciling evidence-based medicine and precision medicine in the era of big data: challenges and opportunities

The importance of copy number variation in congenital heart disease

A National Referral Laboratory’s Experience with the Implementation of SNP-Based Non-invasive Prenatal Screening for Fetal Aneuploidy and Select Microdeletion Syndromes

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