A comprehensive strategy for exome-based preconception carrier screening

Abstract

Purpose: Whole-exome sequencing (WES) provides the possibility of genome-wide preconception carrier screening (PCS). Here, we propose a filter strategy to rapidly identify the majority of relevant pathogenic mutations. Methods:Our strategy was developed using WES data from eight consanguineous and five fictive nonconsanguineous couples and was subsequently applied to 20 other fictive nonconsanguineous couples. Presumably pathogenic variants based on frequency and database annotations or generic characteristics and mutation type were selected in genes shared by the couple and in the female's X-chromosome. Unclassified variants were not included. Results:This yielded an average of 29 (19-51) variants in genes shared by the consanguineous couples and 15 (6-30) shared by the nonconsanguineous couples. For X-linked variants, the numbers per female were 3 (1-5) and 1 (0-3), respectively. Remaining variants were verified manually. The majority were able to be quickly discarded, effectively leaving true pathogenic variants. Conclusion:We conclude that WES is applicable for PCS, both for consanguineous and nonconsanguineous couples, with the remaining number of variants being manageable in a clinical setting. The addition of gene panels for filtering was not favorable because it resulted in missing pathogenic variants. It is important to develop and continuously curate databases with pathogenic mutations to further increase the sensitivity of WES-based PCS.

Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes

“…To our knowledge, few ES studies have been conducted on this topic on individuals with no clinical phenotype (except infertility), and those available are based on small sample sizes [9,10] or are especially focused on consanguineous couples [11]. FDR detected in our ES approach was significantly higher than previous pre-selected gene-panel approaches.…”

“…This approach has critical advantages compared to carrier rate extrapolation from disease prevalence in the postnatal population because this is usually impacted by ascertain bias, in which only severely affected individuals are identified. Further, the use of individual-level data complemented by parallel testing for specific genes instead of aggregated data from population databases [9], confers significant strength and additional reliability to this study’s findings. These population genetics data can be particularly useful for providers and patients assessing and comparing clinical validity among the heterogeneous PCS strategies and gene-disease panels.…”

“…FDR detected in our ES approach was significantly higher than previous pre-selected gene-panel approaches. Exome sequencing aggregated data from gnomAD were recently leveraged by Guo and Gregg to estimate carrier rates across six major ancestries[9]. They showed that screening just the 40 selected genes with carrier rate >1.0% would identify more than 76% of these at-risk couples.…”

Expanded carrier screening for monogenic disorders: where are we now?

“…Accordingly, the use of nontargeted sequencing in the context of carrier screening has been controversial, as this approach may routinely identify novel variants, many of which could be of unclear clinical significance . On the other hand, some novel variants, such as those occurring at canonical splice sites, could be clearly pathogenic with a highly predictable health impact . These may be particularly common in individuals from geographically isolated areas or with ethnic backgrounds where genotype data are sparse.…”

Genetics in mainstream medicine: Finally within grasp to influence healthcare globally

“…It is available globally to everyone interested in preconception screening. In countries with high rates of consanguineous marriage, WES has been proposed as a carrier screen (Sallevelt et al., ).…”