Leveraging diverse genomic data to guide equitable carrier screening: Insights from gnomAD v.4.1.0

Area of Science:

• Genomics
• Medical Genetics
• Population Genetics

Background:

• Carrier screening is crucial for reproductive partners to assess the risk of having children with autosomal-recessive conditions.
• Current guidelines recommend screening for genes with a carrier frequency of at least 1/200 and associated with moderate/severe conditions.

Purpose of the Study:

• To systematically analyze carrier frequencies of pathogenic/likely pathogenic variants in genes linked to autosomal-recessive disorders using gnomAD v.4.1.0 exome data.
• To identify an updated list of candidate genes for carrier screening panels that are equitable across diverse ancestral populations.

Main Methods:

• Analysis of over 700,000 exomes from gnomAD v.4.1.0 across eight ancestries.
• Estimation of carrier frequencies for pathogenic/likely pathogenic variants in 2,987 genes associated with autosomal-recessive conditions.
• Expert curation of identified genes for clinical severity and application of the American College of Medical Genetics and Genomics (ACMG) screening criteria.

Main Results:

• Identified 286 genes meeting the criteria for carrier screening based on carrier frequency and clinical severity.
• Carrier frequencies varied significantly across populations, with notable differences observed (e.g., 40 genes in South Asian vs. 119 in Ashkenazi Jewish ancestry).
• Simulations indicated that pan-ethnic screening panels are advantageous for individuals of diverse or admixed ancestry.

Conclusions:

• The study provides an updated, comprehensive candidate gene list for equitable carrier screening, leveraging the largest exome dataset to date.
• Findings underscore the importance of considering population-specific carrier frequencies for effective genetic screening.
• Emphasizes the need for expanded genomic resources, particularly for underrepresented groups, to improve rare disease risk assessment and screening efforts.