Abstract
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.
Highlights
Trio analysis is recommended to improve diagnostic yield[23] and obtain results faster, which is especially important in the prenatal context.[29]
Susceptibility CNVs, which are associated with both variable expression and variable penetrance, are especially challenging and recommendations strongly differ; if high penetrance neuro-susceptibility loci are found with chromosomal microarray (CMA) that may be associated with a severe phenotype, Gardiner et al recommended reporting these.[28]
This systematic review provides an overview of existing guidelines for dealing with uncertainty in prenatal CMA and exome sequencing (ES)
Summary
Wileyonlinelibrary.com/journal/cge previously undetectable genetic anomalies.[1,2] Currently, some countries are introducing ES in prenatal genetics in cases of fetal malformations,[3,4] generating large amounts of information on the genome of the unborn child compared to karyotyping, CMA or targeted genetic testing panels. This raises the concern for an increased chance of an uncertain finding, such as genes or variants of uncertain significance (GUS/VUS).[5] Filters based on the presenting phenotype and for genes with valid phenotypic associations minimize this uncertainty, but may decrease the diagnostic yield. This systematic review provides an overview of guidelines and recommendations for practice that are available to support professionals dealing with uncertainty in routine clinical prenatal diagnostics
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