Systematic design and comparison of expanded carrier screening panels

Beauchamp, Kyle A.; Muzzey, Dale; Wong, Kenny K.; Hogan, Gregory J.; Karimi, Kambiz; Candille, Sophie I.; Mehta, Nikita; Mar‐Heyming, Rebecca; Kaseniit, Kristjan Eerik; Kang, Hyunseok P.; Evans, E. Edward; Goldberg, James D.; Lazarin, Gabriel A.; Haque, Imran S.

doi:10.1038/gim.2017.69

Cited by 59 publications

(60 citation statements)

References 27 publications

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“…Panel-wide CNVs contributed approximately 9.2% of the assessed MFDR. CNVs in DMD alone represented approximately 6% of the risk, with the remaining genes accounting for approximately 3%, largely consistent with our expectation of CNV-attributable MFDR estimated from the 94-disease panel (10 ). We have observed hundreds of carriers with exon-level deletions (Fig.…”

Section: Resultssupporting

confidence: 88%

“…Genomic technologies like NGS have enabled growth in ECS panel size without incurring a corresponding increase in testing cost, but judicious panel construction and validation are required. For these reasons, we recently published a systematic process for ECS panel design (10 ) and here present an analytical validation of our updated ECS and a modeling analysis of its clinical impact. Our analytical validation study of variants in hundreds of genes across hundreds of samples demonstrates high analytical sensitivity, analytical specificity, and accuracy of genotype calls.…”

Section: Discussionmentioning

confidence: 99%

“…Low complexity sequences (e.g., CGG repeat expansion in FMR1 3 for fragile X syndrome) and highly homologous regions (e.g., SMN1 and SMN2 genes for spinal muscular atrophy) complicate variant identification, yet these hard-to-sequence genes simultaneously contribute substantially to the disease risk. For instance, fragile X syndrome, spinal muscular atrophy, 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH), and ␣-thalassemia account for 54 affected fetuses per 100 000 pregnancies (10 ).…”

confidence: 99%

“…MFDR was a modeled estimate of the probability that a pregnancy was affected by a condition on the panel (it could be summed across diseases to yield an aggregate MFDR of the panel), whereas an ARC, as used herein, was a couple identified empirically as being at high risk for an affected child. Reported MFDR numbers were calculated as described previously (4,10 ) only patients receiving routine carrier screening and, therefore, excluded those with known family history or infertility. By contrast, the reported couple and ARC counts are raw counts, not necessarily representative of the general US population because of the over-representation of high-risk ethnic groups, infertility patients, and patients with family history of disease.…”

Section: Patient Cohortmentioning

confidence: 99%

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Validation of an Expanded Carrier Screen that Optimizes Sensitivity via Full-Exon Sequencing and Panel-wide Copy Number Variant Identification

Hogan¹,

Vysotskaia²,

Beauchamp³

et al. 2018

Clinical Chemistry

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BACKGROUND By identifying pathogenic variants across hundreds of genes, expanded carrier screening (ECS) enables prospective parents to assess the risk of transmitting an autosomal recessive or X-linked condition. Detection of at-risk couples depends on the number of conditions tested, the prevalence of the respective diseases, and the screen's analytical sensitivity for identifying disease-causing variants. Disease-level analytical sensitivity is often <100% in ECS tests because copy number variants (CNVs) are typically not interrogated because of their technical complexity. METHODS We present an analytical validation and preliminary clinical characterization of a 235-gene sequencing-based ECS with full coverage across coding regions, targeted assessment of pathogenic noncoding variants, panel-wide CNV calling, and specialized assays for technically challenging genes. Next-generation sequencing, customized bioinformatics, and expert manual call review were used to identify single-nucleotide variants, short insertions and deletions, and CNVs for all genes except FMR1 and those whose low disease incidence or high technical complexity precluded novel variant identification or interpretation. RESULTS Screening of 36859 patients' blood or saliva samples revealed the substantial impact on fetal disease-risk detection attributable to novel CNVs (9.19% of risk) and technically challenging conditions (20.2% of risk), such as congenital adrenal hyperplasia. Of the 7498 couples screened, 335 were identified as at risk for an affected pregnancy, underscoring the clinical importance of the test. Validation of our ECS demonstrated >99% analytical sensitivity and >99% analytical specificity. CONCLUSIONS Validated high-fidelity identification of different variant types—especially for diseases with complicated molecular genetics—maximizes at-risk couple detection.

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Section: Resultssupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Patient Cohortmentioning

confidence: 99%

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Validation of an Expanded Carrier Screen that Optimizes Sensitivity via Full-Exon Sequencing and Panel-wide Copy Number Variant Identification

Hogan¹,

Vysotskaia²,

Beauchamp³

et al. 2018

Clinical Chemistry

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“…Based on the variant-interpretation concordance analyses presented here and in several previous studies describing the genes selected for inclusion on the panel, 6,21,22 we conclude that the ECS investigated here has sufficient clinical validity for widespread screening.…”

Section: Discussionsupporting

confidence: 65%

Inter‐lab concordance of variant classifications establishes clinical validity of expanded carrier screening

Kaseniit

Collins

et al. 2019

Clinical Genetics

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Expanded carrier screening (ECS) panels that use next‐generation sequencing aim to identify pathogenic variants in coding and clinically relevant non‐coding regions of hundreds of genes, each associated with a serious recessive condition. ECS has established analytical validity and clinical utility, meaning that variants are accurately identified and pathogenic variants tend to alter patients' clinical management, respectively. However, the clinical validity of ECS, that is, correct discernment of whether an identified variant is indeed pathogenic, has only been shown for single conditions, not for panels. Here, we evaluate the clinical validity of a >170‐condition ECS panel by assessing concordance between >12 000 variant interpretations classified with guideline‐based criteria to their corresponding per‐variant combined classifications in ClinVar. We observe 99% concordance at the level of unique variants. A more clinically relevant frequency‐weighted analysis reveals that fewer than 1 in 500 patients are expected to receive a report with a variant that has a discordant classification. Importantly, gene‐level concordance is not diminished for rare ECS conditions, suggesting that large panels do not balloon the panel‐wide false‐positive rate. Finally, because ECS is intended to serve all reproductive‐age couples, we show that classification of novel variants is feasible and scales predictably for a large population.

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Ethical Issues in Multiplex Genetic Testing

Kilbride

Bradbury

2020

Encyclopedia of Life Sciences

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As a result of technological advancements, multiplex (or multigene) genetic tests are increasingly available both inside and outside the clinical setting. Multiplex genetic tests include: expanded carrier screening (ECS), preimplantation genetic testing (PGT), prenatal genetic diagnosis (PND), newborn screening (NBS), predictive genetic testing, diagnostic genetic testing, whole‐genome sequencing (WGS) and whole‐exome sequencing (WES). Many of these tests include dozens – even hundreds – of genes that are associated with a wide range of genetic conditions. While multiplex genetic tests have significant advantages over more targeted approaches, they also raise ethical concerns, related to informed consent, the implications of genetic selection and uncertainty. Outside the clinical setting, direct‐to‐consumer (DTC) genetic testing also raises a set of ethical concerns, including some that are specific to the DTC model. Key Concepts Multiplex genetic testing has important advantages over targeted approaches, including efficiency, cost‐effectiveness and the detection of unanticipated genetic risks. There are different types of multiplex genetic tests. Multiplex genetic testing raises ethical concerns about informed consent, the implications of genetic selection and uncertainty. Obtaining informed consent to multiplex genetic testing is challenging because multiplex tests often analyse genes that are associated with a range of diseases, penetrance estimates and medical management strategies. Genetic testing, particularly of embryos and fetuses, raises ethical concerns about genetic selection for or against certain traits. Multiplex genetic tests can lead to significant uncertainty for patients interested in learning about their own genetic risks or those of their current or future children. Multiplex genetic testing is increasingly available through direct‐to‐consumer (DTC) platforms, raising unique ethical questions about the nature of informed consent outside the clinical setting. In order to realise the promise of multiplex genetic tests, there is a need to continue studying the risks and benefits of different types of tests by collecting and evaluating outcome data.

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Systematic design and comparison of expanded carrier screening panels

Cited by 59 publications

References 27 publications

Validation of an Expanded Carrier Screen that Optimizes Sensitivity via Full-Exon Sequencing and Panel-wide Copy Number Variant Identification

Validation of an Expanded Carrier Screen that Optimizes Sensitivity via Full-Exon Sequencing and Panel-wide Copy Number Variant Identification

Inter‐lab concordance of variant classifications establishes clinical validity of expanded carrier screening

Ethical Issues in Multiplex Genetic Testing

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