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Challenges for the implementation of next generation sequencing-based expanded carrier screening: Lessons learned from the ciliopathies


Vintschger, Ella; Kraemer, Dennis; Joset, Pascal; Horn, Anselm H C; Rauch, Anita; Sticht, Heinrich; Bachmann-Gagescu, Ruxandra (2023). Challenges for the implementation of next generation sequencing-based expanded carrier screening: Lessons learned from the ciliopathies. European Journal of Human Genetics, 31(8):953-961.

Abstract

Next generation sequencing (NGS) can detect carrier status for rare recessive disorders, informing couples about their reproductive risk. The recent ACMG recommendations support offering NGS-based carrier screening (NGS-CS) in an ethnic and population-neutral manner for all genes that have a carrier frequency >1/200 (based on GnomAD). To evaluate current challenges for NGS-CS, we focused on the ciliopathies, a well-studied group of rare recessive disorders. We analyzed 118 ciliopathy genes by whole exome sequencing in ~400 healthy local individuals and ~1000 individuals from the UK1958-birth cohort. We found 20% of healthy individuals (1% of couples) to be carriers of reportable variants in a ciliopathy gene, while 50% (4% of couples) carry variants of uncertain significance (VUS). This large proportion of VUS is partly explained by the limited utility of the ACMG/AMP variant-interpretation criteria in healthy individuals, where phenotypic match or segregation criteria cannot be used. Most missense variants are thus classified as VUS and not reported, which reduces the negative predictive value of the screening test. We show how gene-specific variation patterns and structural protein information can help prioritize variants most likely to be disease-causing, for (future) functional assays. Even when considering only strictly pathogenic variants, the observed carrier frequency is substantially higher than expected based on estimated disease prevalence, challenging the 1/200 carrier frequency cut-off proposed for choice of genes to screen. Given the challenges linked to variant interpretation in healthy individuals and the uncertainties about true carrier frequencies, genetic counseling must clearly disclose these limitations of NGS-CS.

Abstract

Next generation sequencing (NGS) can detect carrier status for rare recessive disorders, informing couples about their reproductive risk. The recent ACMG recommendations support offering NGS-based carrier screening (NGS-CS) in an ethnic and population-neutral manner for all genes that have a carrier frequency >1/200 (based on GnomAD). To evaluate current challenges for NGS-CS, we focused on the ciliopathies, a well-studied group of rare recessive disorders. We analyzed 118 ciliopathy genes by whole exome sequencing in ~400 healthy local individuals and ~1000 individuals from the UK1958-birth cohort. We found 20% of healthy individuals (1% of couples) to be carriers of reportable variants in a ciliopathy gene, while 50% (4% of couples) carry variants of uncertain significance (VUS). This large proportion of VUS is partly explained by the limited utility of the ACMG/AMP variant-interpretation criteria in healthy individuals, where phenotypic match or segregation criteria cannot be used. Most missense variants are thus classified as VUS and not reported, which reduces the negative predictive value of the screening test. We show how gene-specific variation patterns and structural protein information can help prioritize variants most likely to be disease-causing, for (future) functional assays. Even when considering only strictly pathogenic variants, the observed carrier frequency is substantially higher than expected based on estimated disease prevalence, challenging the 1/200 carrier frequency cut-off proposed for choice of genes to screen. Given the challenges linked to variant interpretation in healthy individuals and the uncertainties about true carrier frequencies, genetic counseling must clearly disclose these limitations of NGS-CS.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Genetics
07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > Genetics
Health Sciences > Genetics (clinical)
Uncontrolled Keywords:pregnancy outcome, risk factors, next generation sequencing, expanded carrier screening, medical genetics, NGS-CS, genetic counceling
Language:English
Date:1 August 2023
Deposited On:03 Jan 2023 16:50
Last Modified:28 Apr 2024 01:42
Publisher:Nature Publishing Group
ISSN:1018-4813
Additional Information:ACKNOWLEDGEMENTS We are thankful to all study participants. The 1958 Birth Cohort (NCDS) is managed by the Centre for Longitudinal Studies at the UCL Institute of Education, funded by the Economic and SocialResearch Council (grant ES/M001660/1). Access to these resources was enabled via the 58READIE Project, funded by Wellcome Trust and Medical Research Council (grants WT095219MA and G1001799). A full list of the financial, institutional, and personal contributions to the development of the 1958 Birth Cohort Biomedical resource is available at www.cls.ioe.ac.uk/ncds).
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41431-022-01267-8
PubMed ID:36550190
Project Information:
  • : FunderUniversity of Zurich UZH
  • : Grant IDCRPP praeclare - Personalized prenatal and reproductive medicine
  • : Project TitleClinical Research Priority Program Praeclare - Personalized prenatal and reproductive medicine
  • : Project Websitehttps://www.praeclare.uzh.ch/
  • : FunderSwiss National Science Foundation (SNSF)
  • : Grant ID170681
  • : Project TitleUnderstanding the molecular mechanisms underlying phenotypic variability in ciliopathies
  • : Project Websitehttps://data.snf.ch/grants/grant/170681
  • : FunderSwiss National Science Foundation (SNSF)
  • : Grant ID198895
  • : Project TitleUnderstanding the molecular mechanisms underlying phenotypic variability in ciliopathies
  • : Project Websitehttps://data.snf.ch/grants/grant/198895
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)