How to deal with uncertainty in prenatal genomics: A systematic review of guidelines and policies

Jasmijn E. Klapwijk, Malgorzata I. Srebniak, Attie T.J.I. Go, Lutgarde C.P. Govaerts, Celine Lewis, Jennifer Hammond, Melissa Hill, Stina Lou, Ida Vogel, Kelly E. Ormond, Karin E.M. Diderich, Hennie T. Brüggenwirth, Sam R. Riedijk

Research output: Contribution to journalReview articleAcademicpeer-review

10 Citations (Scopus)


Exome sequencing (ES) enhanced the diagnostic yield of genetic testing, but has also increased the possibility of uncertain findings. Prenatal ES is increasingly being offered after a fetal abnormality is detected through ultrasound. It is important to know how to handle uncertainty in this particularly stressful period. This systematic review aimed to provide a comprehensive overview of guidelines available for addressing uncertainty related to prenatal chromosomal microarray (CMA) and ES. Ten uncertainty types associated with prenatal ES and CMA were identified and defined by an international multidisciplinary team. Medline (all) and Embase were systematically searched. Laboratory scientists, clinical geneticists, psychologists, and a fetal medicine specialist screened the papers and performed the data extraction. Nineteen papers were included. Recommendations generally emphasized the importance of trio analysis, clinical information, data sharing, validation and re-analysis, protocols, multidisciplinary teams, genetic counselling, whether to limit the possible scope of results, and when to report particular findings. This systematic review helps provide a vocabulary for uncertainties, and a compass to navigate uncertainties. Prenatal CMA and ES guidelines provide a strong starting point for determining how to handle uncertainty. Gaps in guidelines and recommendations were identified and discussed to provide direction for future research and policy making.

Original languageEnglish
Pages (from-to)647-658
Number of pages12
JournalClinical genetics
Issue number6
Publication statusPublished - Dec 2021


  • chromosomal microarray
  • health planning guidelines
  • health policy
  • practice guidelines
  • prenatal diagnosis
  • uncertainty
  • whole exome sequencing

Cite this