Dataset Information

Assessment of an automated approach for variant interpretation in screening for monogenic disorders: A single-center study.

ABSTRACT:

Background

Automation has been introduced into variant interpretation, but it is not known how automated variant interpretation performs on a stand-alone basis. The purpose of this study was to evaluate a fully automated computerized approach.

Method

We reviewed all variants encountered in a set of carrier screening panels over a 1-year interval. Observed variants with high-confidence ClinVar interpretations were included in the analysis; those without high-confidence ClinVar entries were excluded.

Results

Discrepancy rates between automated interpretations and high-confidence ClinVar entries were analyzed. Of the variants interpreted as positive (likely pathogenic or pathogenic) based on ClinVar information, 22.6% were classified as negative (variants of uncertain significance, likely benign or benign) variants by the automated method. Of the ClinVar negative variants, 1.7% were classified as positive by the automated software. On a per-case basis, which accounts for variant frequency, 63.4% of cases with a ClinVar high-confidence positive variant were classified as negative by the automated method.

Conclusion

While automation in genetic variant interpretation holds promise, there is still a need for manual review of the output. Additional validation of automated variant interpretation methods should be conducted.

SUBMITTER: Gall BJ

PROVIDER: S-EPMC9747559 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

Assessment of an automated approach for variant interpretation in screening for monogenic disorders: A single-center study.

Gall Bryan J BJ Smart Trevor B TB Munch Robin R Kolluri Supraja S Tadepally Hamsa H Lim Karen Phaik Har KPH Demko Zachary P ZP Benn Peter P Souter Vivienne V Sanapareddy Nina N Keen-Kim Dianne D

Molecular genetics & genomic medicine 20221105 12

<h4>Background</h4>Automation has been introduced into variant interpretation, but it is not known how automated variant interpretation performs on a stand-alone basis. The purpose of this study was to evaluate a fully automated computerized approach.<h4>Method</h4>We reviewed all variants encountered in a set of carrier screening panels over a 1-year interval. Observed variants with high-confidence ClinVar interpretations were included in the analysis; those without high-confidence ClinVar entr ...[more]

PMID: 36333997

Similar Datasets

Project description:Introduction: Circulating fetal cells isolated from maternal blood can be used for prenatal testing, representing a safe alternative to invasive testing. The present study investigated the potential of cell-based noninvasive prenatal testing (NIPT) for diagnosing monogenic disorders dependent on the mode of inheritance. Methods: Maternal blood samples were collected from women opting for prenatal diagnostics for specific monogenic disorders (N = 7). Fetal trophoblasts were enriched and stained using magnetic activated cell sorting and isolated by fluorescens activated single-cell sorting. Individual cells were subject to whole genome amplification, and cells of fetal origin were identified by DNA-profiling using short tandem repeat markers. The amplified fetal DNA was input for genetic testing for autosomal dominant-, autosomal recessive-, X-linked and repeat expansion disorders by direct variant analysis and haplotyping. The cell-based NIPT results were compared with those of invasive testing. Results: In two cases at risk of skeletal dysplasia, caused by variants in the FGFR3 gene (autosomal dominant disorders), cell-based NIPT correctly stated an affected fetus, but allelic dropout of the normal alleles were observed in both cases. Cell-based NIPT gave an accurate result in two cases at risk of autosomal recessive disorders, where the parents carried either different diastrophic dysplasia causing variants in the SLC26A2 gene or the same cystic fibrosis disease-causing variant in the CFTR gene. Cell-based NIPT accurately identified an affected male fetus in a pregnancy at risk of Duchenne muscular dystrophy (DMD gene, X-linked recessive disorders). In two cases at risk of the myotonic dystrophy type 1 (DMPK gene, repeat expansion disorder), cell-based NIPT correctly detected an affected and an unaffected fetus, respectively. Discussion: Circulating fetal cells can be used to detect both maternally- and paternally inherited monogenic disorders irrespective of the type of variant, however, the risk of allelic dropout must be considered. We conclude that the clinical interpretation of the cell-based NIPT result thus varies depending on the disorders' mode of inheritance.

Dataset Information

Assessment of an automated approach for variant interpretation in screening for monogenic disorders: A single-center study.

Background

Method

Results

Conclusion

Publications

Assessment of an automated approach for variant interpretation in screening for monogenic disorders: A single-center study.

Similar Datasets

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