Expanded carrier screening for inherited genetic disease using exome and genome sequencing

Area of Science:

• Genomics
• Reproductive Medicine
• Genetic Screening

Background:

• Current preconception genetic screening (PCGS) relies on limited gene panels, potentially missing couples at risk for rare autosomal recessive (AR) and X-linked (XL) disorders.
• The need for a more comprehensive approach to identify at-risk couples before conception is critical for informed family planning.

Purpose of the Study:

• To evaluate the feasibility of using exome sequencing (ES) and genome sequencing (GS) for PCGS.
• To develop a workflow for identifying risk alleles for AR and XL disorders without predefined gene panels.
• To compare the efficacy of ES/GS with current ACMG-recommended carrier screening panels.

Main Methods:

• Analysis of pre-existing, de-identified exome and genome sequencing data from 150 families (trios).
• Identification of parental variants associated with risk for AR and XL disorders.
• Comparison of identified at-risk couples with those detected by standard ACMG-recommended gene panels.

Main Results:

• Out of 150 couples, 17 families were identified as being at risk for AR or XL disorders.
• Only 3 of these 17 at-risk couples would have been identified using current ACMG-recommended carrier screening panels.
• ES and GS successfully identified couples at risk for rare AR/XL disorders missed by current guidelines.

Conclusions:

• Exome and genome sequencing are feasible for comprehensive preconception genetic screening, significantly improving the detection of at-risk couples.
• This approach identifies a greater number of couples at risk for rare genetic disorders compared to standard gene panels.
• Challenges remain in reporting, variant calling for rare variants, determining reportable disorders, and technical limitations like repeat expansions.