Community data-driven approach to identify pathogenic founder variants for pan-ethnic carrier screening panels

Area of Science:

• Genetics
• Bioinformatics
• Public Health

Background:

• New American College of Medical Genetics and Genomics (ACMG) guidelines recommend tier-based carrier screening.
• Pathogenic founder variants (PFVs) are often specific to certain ethnic groups.
• Existing screening panels may not cover all relevant genetic disorders for diverse populations.

Purpose of the Study:

• To demonstrate a community data-driven approach for developing a pan-ethnic carrier screening panel.
• To align carrier screening with ACMG recommendations.
• To identify novel PFVs in underrepresented ethnic groups.

Main Methods:

• Exome sequencing data from 3061 Israeli individuals were analyzed.
• Machine learning was used for ancestry determination and variant frequency calculation.
• Candidate PFVs were curated using community data (Franklin platform) and literature review.

Main Results:

• Samples were assigned to 13 ancestries, with Ashkenazi Jewish and Muslim Arab being the largest groups.
• Seven tier-3 and one tier-2 variants, absent in current panels, were identified for these ancestries.
• Five of these variants were validated by community evidence; 20 additional potentially pathogenic variants were detected.

Conclusions:

• Community data-driven and sharing approaches enable the creation of inclusive and equitable ethnically based carrier screening panels.
• This method successfully identified novel PFVs not present in existing screening panels.
• The findings highlight the need for reclassification of certain genetic variants and improved ethnic representation in screening.