Clinical experience with multigene carrier panels in the reproductive setting

Terhaar, Catherine; Teed, Nicole; Allen, Rachel; Dohany, Lindsay; Settler, Christina; Holland, Carol; Longman, Ryan E.

doi:10.1002/pd.5272

Cited by 10 publications

(5 citation statements)

References 11 publications

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“…Our findings are consistent with the expectation and previous reports that increasing the number of genes in a panel results in an increase in the number of individuals identified as carriers for a single genetic condition and for individuals identified as carriers for multiple genetic conditions (Arjunan et al, ; Baskovich et al, ; Haque et al, ; Lazarin et al, ; Terhaar et al, ). Our pan‐ethnic expanded carrier screening panel of 87 genes increased the carrier detection rate among AJ individuals by approximately 50% compared with the 18‐gene AJ panel and by approximately 100% compared with the nine ACMG genes recommended for AJ carrier screening.…”

Section: Discussionsupporting

confidence: 93%

“…Baskovich et al () analyzed exome data for 128 AJ individuals and identified 163 mutations causing 103 conditions, but the intent was to identify new pathogenic mutations to include in an AJ panel, not to specify which positive results would have been obtained with a recommended AJ panel. Terhaar et al () detailed a commercial laboratory's experience using three different carrier screening panels, comparing positive rates for patients tested for carrier status for either three, 23, or 218 conditions. The population was pan‐ethnic, with nearly half identified as Caucasian and fewer than 0.5% (322 of approximately 75,000 individuals) as AJ.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of pan‐ethnic and ethnic‐based carrier screening panels for individuals of Ashkenazi Jewish descent

Rosenblum

Zhu

Zhou

et al. 2019

Journal of Genetic Counseling

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The intent of carrier screening is to identify individuals at risk for having a child with a genetic disorder. American College of Medical Genetics and Genomics (ACMG) guidelines currently recommend that individuals of Ashkenazi Jewish (AJ) descent be screened for carrier status for nine disorders. However, a joint statement from five professional organizations acknowledges benefits of expanded carrier screening and this is becoming common practice. To better understand the impact of expanded carrier screening for the AJ population, we performed a retrospective analysis comparing detection rates for AJ individuals screened by two targeted panels: a pan‐ethnic panel comprising 87 disorders and an AJ panel comprising an 18‐disorder subset of the pan‐ethnic panel. We also extrapolated the detection rates for the 18 AJ disorders from the pan‐ethnic panel data and for the nine ACMG‐recommended disorders using data from both panels. We found that with the pan‐ethnic panel 431/1150 (37.5%) individuals were carriers of at least one disorder, compared to 319/1248 (25.6%) individuals with the AJ panel. If the pan‐ethnic panel cohort were tested in the AJ panel or for the nine ACMG‐recommended disorders, the detection rates would have been 280/1150 (24.3%) and 207/1150 (18.0%) respectively. Therefore, the pan‐ethnic expanded carrier screening panel of 87 disorders increased the carrier detection rate in AJ individuals by approximately 50% and 100%, respectively, compared with a panel of 18 disorders considered relevant to the AJ population and the ACMG‐recommended disorders. Twenty disorders accounted for the difference in carrier detection rates between the pan‐ethnic and AJ panels. Of these, three were among the 10 most commonly identified disorders. Our findings reinforce published data that targeted AJ panels are less effective than a pan‐ethnic panel in carrier detection among AJ individuals and provide metrics to address the impact of expanded carrier screening in this population.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Comparison of pan‐ethnic and ethnic‐based carrier screening panels for individuals of Ashkenazi Jewish descent

Rosenblum

Zhu

Zhou

et al. 2019

Journal of Genetic Counseling

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“…For individuals of AJ origin, the CCR found in our study was 58.5% and therefore higher than the 37.5% (1:2.7) 19 and 40% (1:2.5) 20 published in AJ cohorts, or the 36% (1:2.8) 21 reported in a pan‐ethnic population.…”

Section: Discussioncontrasting

confidence: 75%

Pathogenic variant‐based preconception carrier screening in the Israeli Jewish population

et al. 2022

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Preconception carrier screening allows identification of couples at risk to have offspring with autosomal recessive and X‐linked disorders. In a current multiethnic world, screening based on self‐reported ancestry has limitations. Here we describe the findings of a comprehensive pan‐ethnic variant‐based carrier screening, using the Israeli Jewish population as a model. The cohort included 1696 individuals (848 couples) tested with the ‘MyScreen’ multigene panel. The panel covers 1206 variants spanning 385 genes, known in different Jewish ethnicities and local Arab, Druze and Bedouin populations. Out of these, 205 variants in 143 genes are Jewish founder variants. We identified 859 (50.6%), carriers of at least one variant in 151 genes. Importantly, 569 (66.2%) of carriers could be missed by the current Israeli screening program. In total, 1:40 (2.5%) of carrier couples were identified by the ‘MyScreen’ panel, compared with 1:144 (0.7%) found by the ethnicity‐based screening. Surprisingly, 90 individuals (10.5%) were carriers of variants “unexpected” for their reported origin, and 16 variants were previously unreported in Jewish patients. Our results support the advantages of variant‐based comprehensive carrier screening for detection of carriers and at‐risk couples in a diverse population with many founder disease‐causing variants.

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“…Applications for WES and targeted DNA (panel) sequencing (n=169, 24%) include identification of pathogenic mutations (mostly point mutations, small insertions and deletions) that can aid in diagnosis of monogenic autoinflammatory diseases and vasculitis, 48 FMF, 49 gout 50 or familial RA, SLE and primary Sjögren’s syndrome 51 or Uveitis. 52 Of note, while HTS assays are powerful tools for large cohorts, we find many case reports using WES and gene panel sequencing in, for example, in a young patient with cutaneous vasculitis 53 or JIA, 54 as well as in a patient with RA experiencing immune dysregulation syndrome after abatacept therapy.…”

Section: Resultsmentioning

confidence: 99%

Current status of use of high throughput nucleotide sequencing in rheumatology

Boegel

Castle²,

Schwarting

2021

RMD Open

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ObjectiveHere, we assess the usage of high throughput sequencing (HTS) in rheumatic research and the availability of public HTS data of rheumatic samples.MethodsWe performed a semiautomated literature review on PubMed, consisting of an R-script and manual curation as well as a manual search on the Sequence Read Archive for public available HTS data.ResultsOf the 699 identified articles, rheumatoid arthritis (n=182 publications, 26%), systemic lupus erythematous (n=161, 23%) and osteoarthritis (n=152, 22%) are among the rheumatic diseases with the most reported use of HTS assays. The most represented assay is RNA-Seq (n=457, 65%) for the identification of biomarkers in blood or synovial tissue. We also find, that the quality of accompanying clinical characterisation of the sequenced patients differs dramatically and we propose a minimal set of clinical data necessary to accompany rheumatological-relevant HTS data.ConclusionHTS allows the analysis of a broad spectrum of molecular features in many samples at the same time. It offers enormous potential in novel personalised diagnosis and treatment strategies for patients with rheumatic diseases. Being established in cancer research and in the field of Mendelian diseases, rheumatic diseases are about to become the third disease domain for HTS, especially the RNA-Seq assay. However, we need to start a discussion about reporting of clinical characterisation accompany rheumatological-relevant HTS data to make clinical meaningful use of this data.

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Clinical experience with multigene carrier panels in the reproductive setting

Cited by 10 publications

References 11 publications

Comparison of pan‐ethnic and ethnic‐based carrier screening panels for individuals of Ashkenazi Jewish descent

Comparison of pan‐ethnic and ethnic‐based carrier screening panels for individuals of Ashkenazi Jewish descent

Pathogenic variant‐based preconception carrier screening in the Israeli Jewish population

Current status of use of high throughput nucleotide sequencing in rheumatology

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