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Original research
Experience using singleton exome sequencing of probands as an approach to preconception carrier screening in consanguineous couples
  1. Anna Abulí1,2,
  2. Mar Costa-Roger1,2,
  3. Marta Codina-Solà1,2,
  4. Irene Valenzuela1,2,
  5. Jordi Leno-Colorado1,2,
  6. Eulàlia Rovira-Moreno1,2,
  7. Anna Cueto-González1,2,
  8. Paula Fernández-Álvarez1,2,
  9. Elena García-Arumí1,2,3,
  10. Ivon Cuscó1,2,3,
  11. Eduardo F Tizzano1,2
  1. 1Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Barcelona, Spain
  2. 2Medicine Genetics Group Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
  3. 3Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
  1. Correspondence to Dr Anna Abulí, Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Barcelona, Spain; anna.abuli{at}vallhebron.cat

Abstract

Background Consanguineous couples have an increased risk of severe diseases in offspring due to autosomal recessive disorders. Exome sequencing (ES) offers the possibility of extensive preconception carrier screening (PCS) in consanguineous couples who may be at risk of rare genetic disorders.

Methods We retrospectively analysed ES data from 65 probands affected with rare genetic disorders born from consanguineous couples. We explored diagnostic yield and carrier status for recessive disorders.

Results The overall diagnostic yield in a singleton approach was 53.8%, mostly recessive variants. In a hypothetical exome-based PCS, only 11.7% of these causative rare variants would have been missed in the filtering process. Carrier screening for recessive conditions allowed the identification of at least one additional pathogenic or likely pathogenic variant in 85.7% of the probands, being the majority with a gene carrier frequency <1 in 200. In addition, considering only clinically actionable conditions, we estimated that 12.3% of our close consanguineous couples may be at risk for an additional recessive disease.

Conclusions Our results demonstrate that ES outperforms panel-based screening in a PCS context in consanguineous couples and could potentially increase their reproductive autonomy and facilitate informed decision-making.

  • consanguinity
  • genetic carrier screening
  • genetic counseling
  • human genetics
  • reproductive medicine

Data availability statement

All data and scripts used to generate the analyses of this paper are available on request unless the type of request compromises ethical standards or legal requirements.

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Data availability statement

All data and scripts used to generate the analyses of this paper are available on request unless the type of request compromises ethical standards or legal requirements.

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Footnotes

  • Contributors Conceptualisation: AA, IC, IV, EFT; data curation: JL, AA, MC-R, MC-S, IV, EG-A, IC; formal analysis: AA, MC-R, MC-S, IV, IC; writing—original draft: AA, MC-R, IC, EFT; writing—review and editing: all authors; guarantor: EFT.

  • Funding This work was partially funded by grants from Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias and co‐funded with ERDF funds: grant no. FIS PI18/000687 (to EFT), grant no. FIS PI19/01772 (to EG-A) and grant no. FIS PI20/01767 (to AC-G).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.