Systematic design and comparison of expanded carrier screening panels

Genet Med. 2018 Jan;20(1):55-63. doi: 10.1038/gim.2017.69. Epub 2017 Jun 22.

Abstract

PurposeThe recent growth in pan-ethnic expanded carrier screening (ECS) has raised questions about how such panels might be designed and evaluated systematically. Design principles for ECS panels might improve clinical detection of at-risk couples and facilitate objective discussions of panel choice.MethodsGuided by medical-society statements, we propose a method for the design of ECS panels that aims to maximize the aggregate and per-disease sensitivity and specificity across a range of Mendelian disorders considered serious by a systematic classification scheme. We evaluated this method retrospectively using results from 474,644 de-identified carrier screens. We then constructed several idealized panels to highlight strengths and limitations of different ECS methodologies.ResultsBased on modeled fetal risks for "severe" and "profound" diseases, a commercially available ECS panel (Counsyl) is expected to detect 183 affected conceptuses per 100,000 US births. A screen's sensitivity is greatly impacted by two factors: (i) the methodology used (e.g., full-exon sequencing finds more affected conceptuses than targeted genotyping) and (ii) the detection rate of the screen for diseases with high prevalence and complex molecular genetics (e.g., fragile X syndrome).ConclusionThe described approaches enable principled, quantitative evaluation of which diseases and methodologies are appropriate for pan-ethnic expanded carrier screening.

MeSH terms

  • Female
  • Genetic Association Studies
  • Genetic Carrier Screening / methods*
  • Genetic Carrier Screening / standards*
  • Genetic Diseases, Inborn / diagnosis*
  • Genetic Diseases, Inborn / genetics*
  • Genetic Predisposition to Disease
  • Genetic Testing / methods
  • Genetic Testing / standards
  • Genomics / methods
  • Genomics / standards
  • Guideline Adherence
  • Humans
  • Reproducibility of Results