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Assessing clinical utility of preconception expanded carrier screening regarding residual risk for neurodevelopmental disorders


Boonsawat, Paranchai; Horn, Anselm H C; Steindl, Katharina; Baumer Wolz, Alessandra; Joset, Pascal; Kraemer, Dennis; Bahr, Angela; Ivanovski, Ivan; Cabello Ferrete, Elena; Papik, Michael; Zweier, Markus; Oneda, Beatrice; Sirleto, Pietro; Burkhardt, Tilo; Sticht, Heinrich; Rauch, Anita (2022). Assessing clinical utility of preconception expanded carrier screening regarding residual risk for neurodevelopmental disorders. n p j Genomic Medicine, 7(1):45.

Abstract

The magnitude of clinical utility of preconception expanded carrier screening (ECS) concerning its potential to reduce the risk of affected offspring is unknown. Since neurodevelopmental disorders (NDDs) in their offspring is a major concern of parents-to-be, we addressed the question of residual risk by assessing the risk-reduction potential for NDDs in a retrospective study investigating ECS with different criteria for gene selection and definition of pathogenicity.
We used exome sequencing data from 700 parents of children with NDDs and blindly screened for carrier-alleles in up to 3046 recessive/X-linked genes. Depending on variant pathogenicity thresholds and gene content, NDD-risk-reduction potential was up to 43.5% in consanguineous, and 5.1% in nonconsanguineous couples.
The risk-reduction-potential was compromised by underestimation of pathogenicity of missense variants (false-negative-rate 4.6%), inherited copy-number variants and compound heterozygosity of one inherited and one de novo variant (0.9% each).
Adherence to the ACMG recommendations of restricting ECS to high-frequency genes in nonconsanguineous couples would more than halve the detectable inherited NDD-risk.
Thus, for optimized clinical utility of ECS, screening in recessive/X-linked genes regardless of their frequency (ACMG Tier-4) and sensible pathogenicity thresholds should be considered for all couples seeking ECS.

Abstract

The magnitude of clinical utility of preconception expanded carrier screening (ECS) concerning its potential to reduce the risk of affected offspring is unknown. Since neurodevelopmental disorders (NDDs) in their offspring is a major concern of parents-to-be, we addressed the question of residual risk by assessing the risk-reduction potential for NDDs in a retrospective study investigating ECS with different criteria for gene selection and definition of pathogenicity.
We used exome sequencing data from 700 parents of children with NDDs and blindly screened for carrier-alleles in up to 3046 recessive/X-linked genes. Depending on variant pathogenicity thresholds and gene content, NDD-risk-reduction potential was up to 43.5% in consanguineous, and 5.1% in nonconsanguineous couples.
The risk-reduction-potential was compromised by underestimation of pathogenicity of missense variants (false-negative-rate 4.6%), inherited copy-number variants and compound heterozygosity of one inherited and one de novo variant (0.9% each).
Adherence to the ACMG recommendations of restricting ECS to high-frequency genes in nonconsanguineous couples would more than halve the detectable inherited NDD-risk.
Thus, for optimized clinical utility of ECS, screening in recessive/X-linked genes regardless of their frequency (ACMG Tier-4) and sensible pathogenicity thresholds should be considered for all couples seeking ECS.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
04 Faculty of Medicine > Institute of Medical Genetics
04 Faculty of Medicine > University Hospital Zurich > Clinic for Gynecology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Obstetrics
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:genetic testing, preventive medicine
Language:English
Date:29 July 2022
Deposited On:03 Aug 2022 11:32
Last Modified:27 Apr 2024 01:38
Publisher:Nature Publishing Group
ISSN:2056-7944
Additional Information:Data availability Data that support the findings of this study are available in the supplementary tables. Due to the limitations of the ethics approval and informed consent signed by the participants, the raw exome sequencing data used for this study cannot be deposited into a public repository; however, ethical approval and consent does allow for data sharing but only in the context of an approved study collaboration. These raw data are available from the SwissGenVar database (https://sphn.ch/network/projects/infrastructure-development-projects/project-page-swissgenvar/). Requests for access to these data must comply consortium rules and require a Data Transfer and Use Agreement, as well as ethical approval for the usage of these data. Correspondence and requests for access to these data should be addressed to swissgenvar@medgen.uzh.ch. Code availability NextGene V2.4.2.3 (Softgenetics Inc.), Automap v1.0, SwissProt (accessed at https://swissmodel.expasy.org/repository on 2 April 2020), ModBase (accessed at https://salilab.org/modbase-download/ on 9 November 2019), PFAM (accessed at http://hmmer.org on 30 March 2020), LASER version 2.04 (https://laser.sph.umich.edu/index.html#!), and R version 4.1.0, ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/, 28 March 2021), HGMD Professional 2021 (Qiagen Inc.), VIPUR (accessed at https://osf.io/bd2h4/ on 28 March 2018); SIFT, PolyPhen2, LRT, MutationTaster, MutationAccessor, FATHMM, PROVEAN, M.CAP, and CADD score (embedded in NextGene V2.4.2.3). Variant filtering was conducted using custom code in R (4.1.0), which is available upon reasonable request.
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41525-022-00316-x
PubMed ID:35906228
Project Information:
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)
  • Content: Supplemental Material
  • Language: English
  • Description: Suppl. Material