Promises, pitfalls and practicalities of prenatal whole exome sequencing

Best, Sunayna; Wou, Karen; Vora, Neeta L.; Veyver, Ignatia B. Van der; Wapner, Ronald J.; Chitty, Lyn S.

doi:10.1002/pd.5102

Cited by 289 publications

(376 citation statements)

References 76 publications

(90 reference statements)

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“…In line with previous studies [16,17], this study indicates that training and education play a major role in the successful completion of a detailed US examination and that the optimal time for a first-trimester scan is 12-13 weeks [18,19], when most fetal organs are sufficiently developed [14,20,21], their visualization can be complete in 86% of cases [22], the majority of spontaneous losses have already occurred (from 81 at 11 weeks to 13 at 13 weeks) [23], and only 3% may still occur thereafter [24]. In a previous prospective study by our group, we showed that when sonographers are instructed to perform a survey of fetal anatomy at the early scan, the detection rate can increase to 45% [4].…”

Section: Discussionsupporting

confidence: 72%

Early Detection of Structural Anomalies in a Primary Care Setting in the Netherlands

Bardi

Smith²,

Kuilman³

et al. 2018

Fetal Diagn Ther

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Objective: This study assessed the percentage and type of congenital anomalies diagnosed at first-trimester ultrasound (US) scan in a primary care setting without following a standardized protocol for fetal anatomical assessment. Materials and Methods: US scans performed between 11⁺⁰ and 13⁺⁶ weeks of gestation in pregnancies with estimated date of delivery between January 1, 2012 and January 1, 2016 were searched. Data were supplemented with results of 20-week scans and pregnancy outcome. Results: Of all scans, 38.6% were dating scans and 61.4% were part of first-trimester screening. Anomalies were diagnosed prenatally in 200 (1.8%) fetuses; 81 (0.7%) were chromosomal and 119 (1.1%) were structural. Of all prenatally detected anomalies, 27% (n = 32) were detected at first-trimester scan, with a false-positive rate of 0.04%. All cases of anencephaly (n = 4), encephalocele (n = 2), exomphalos (n = 9), megacystis (n = 4), and limb reduction (n = 1) were diagnosed. First-trimester detection of gastroschisis and congenital heart defects was 67 and 19%, respectively. Conclusion: In a primary care setting, global fetal anatomical assessment at first-trimester scan without following a standardized protocol detects about 30% of all structural anomalies and most of the severe anomalies, with an extremely low false-positive rate. We hypothesize that additional training and use of a systematic protocol would improve early detection of structural anomalies.

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Section: Discussionsupporting

confidence: 72%

Early Detection of Structural Anomalies in a Primary Care Setting in the Netherlands

Bardi

Smith²,

Kuilman³

et al. 2018

Fetal Diagn Ther

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“…In targeting specific trios for testing, the diagnostic rate with WES was 80%. This is higher than previously reported in the literature for ultrasound anomalies (Alamillo, ; Best et al, ; Carss et al, ; Drury et al, ; Pangalos et al, ).…”

Section: Discussioncontrasting

confidence: 51%

“…Multiple experts have commented on the “Pandora's box” effect of whole exome analysis (Best et al, ; Quinlan‐Jones et al, ). This applies to variants of unknown significance (VOUS) as well as secondary findings in the parents.…”

Section: Discussionmentioning

confidence: 99%

“…While many fetal anomalies will have no identifiable genetic cause, WES can improve the diagnosis rate in cases with normal microarray. The reported yield for whole exome with a fetal anomaly on ultrasound ranges from 6.2% to 57% (Alamillo, ; Best et al, ; Carss et al, ; Drury et al (); Pangalos, Hagnefelt, Lilakos, & Konialis, ). In each of these reports, WES was done after initial studies with karyotype and microarray were normal.…”

Section: Introductionmentioning

confidence: 99%

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Whole exome sequencing for prenatal diagnosis in cases with fetal anomalies: Criteria to improve diagnostic yield

Yadava

Ashkinadze

2018

Journal of Genetic Counseling

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Whole exome sequencing (WES) for prenatal diagnosis has a reported diagnostic yield of 6.2%–57%. Our aim was to identify patients with a high likelihood of genetic diagnosis using WES in cases with fetal ultrasound anomalies. This is a series of five selected cases for prenatal WES at our institution. Pregnant couples were initially identified due to fetal ultrasound anomalies. Candidates for WES for fetal diagnosis had a normal fetal karyotype and negative microarray with at least one of the following: parental consanguinity, large regions of homozygosity on fetal microarray, or high likelihood of single gene disorder based on ultrasound findings. All trios underwent sequencing of parental and fetal samples. WES was diagnostic in four of the five cases (80%). We identified two recessive conditions and two de novo mutations. Four couples consented to secondary findings and in one case, the father was found to have an MSH2 mutation associated with Lynch syndrome. The use of specific selection criteria for WES increased diagnostic yield to 80%. This is higher than previously reported. Wide application of our criteria can help identify those who may benefit most from this testing in prenatal diagnosis.

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“…This kind of tradeoff would come into play when confronting the possibility of learning about numerous genetic conditions, each with different clinical outcomes (e.g., age of onset, phenotype, penetrance, and expressivity) and test associated characteristics (e.g., detection rate and positive predictive value for each condition). This process would also be of importance when determining what thresholds of uncertainty could be tolerated by the patient and family in the process of testing (Bernhardt et al, ; Walser, Werner‐Lin, Russell, Wapner, & Bernhardt, ), most notably when individualized outcomes could not be determined until after birth (Aarabi et al, ; Best et al, ; Bianchi et al, ; Wapner, Driscoll, & Simpson, ). While this finding was noted in our study population, important questions remain about the role of values in women of different age and reproductive history groups in conjunction with advances in cfDNA capability.…”

Section: Discussionmentioning

confidence: 99%

The personal utility of cfDNA screening: Pregnant patients' experiences with cfDNA screening and views on expanded cfDNA panels

Farrell

Agatisa

Michie

et al. 2019

Journal of Genetic Counseling

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Prenatal cell‐free DNA screening (cfDNA) provides more genetic risk information about the fetus than has ever been possible. At the same time, the rapid expansion of new cfDNA panels raises important questions about how to structure patient‐centered discussions that best support patients' decision‐making about its use. To address this question, we conducted interviews with pregnant patients to identify decision‐making needs and preferences with respect to cfDNA in patient‐centered healthcare discussions, given its evolving capability to identify a range of fetal variants. Personal utility was a core concept guiding decision‐making. Participants spoke of how their deeply personal values and beliefs about maternal responsibility, actionability, and tolerance of uncertainty framed their view of the personal utility of cfDNA screening. While discussing their notions of personal utility with their healthcare provider, participants also had concerns about potential ramifications for the provider–patient relationship and shared decision‐making when disclosing values and preferences regarding disability, quality of life, and termination—particularly as it becomes possible to identify variants with different disease‐associated severity and outcomes. The complexities associated with the introduction of genomics in prenatal care present unique challenges to structuring effective shared decision‐making discussions between patients and their healthcare providers. While efforts are underway to determine how to best educate patients about the medical aspects of cfDNA, it is equally important to develop approaches in healthcare communication that enable patients to make informed, values‐based decisions about the use of cfDNA and its impact on their pregnancy.

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Promises, pitfalls and practicalities of prenatal whole exome sequencing

Cited by 289 publications

References 76 publications

Early Detection of Structural Anomalies in a Primary Care Setting in the Netherlands

Early Detection of Structural Anomalies in a Primary Care Setting in the Netherlands

Whole exome sequencing for prenatal diagnosis in cases with fetal anomalies: Criteria to improve diagnostic yield

The personal utility of cfDNA screening: Pregnant patients' experiences with cfDNA screening and views on expanded cfDNA panels

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