The burden of pathogenic variants in clinically actionable genes in a founder population

• Published in: American journal of medical genetics. Part A Vol. 185; no. 11; pp. 3476 - 3484
• Main Authors: Lynch, Megan T., Maloney, Kristin A., Pollin, Toni I., Streeten, Elizabeth A., Xu, Huichun, Shuldiner, Alan R., Van Hout, Cristopher V., Gonzaga‐Jauregui, Claudia, Mitchell, Braxton D.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.11.2021; Wiley Subscription Services, Inc
• Subjects: Adult; Amish - genetics; Exome - genetics; exome sequencing; Female; founder populations; Genetic Diseases, Inborn - diagnosis; Genetic Diseases, Inborn - epidemiology; Genetic Diseases, Inborn - genetics; Genetic diversity; Genetic drift; Genetic Predisposition to Disease; Genetic Testing; Genetic Variation - genetics; genomic medicine; Genomics; Humans; Male; Middle Aged; Precision Medicine; Quality control; secondary findings; Whole Exome Sequencing; genomic medicine; exome sequencing; secondary findings; genetic testing; founder populations
• ISSN: 1552-4825; 1552-4833; 1552-4833
• DOI: 10.1002/ajmg.a.62472

Founder populations may be enriched with certain genetic variants of high clinical impact compared to nonfounder populations due to bottleneck events and genetic drift. Using exome sequencing (ES), we quantified the load of pathogenic variants that may be clinically actionable in 6136 apparently healthy adults living in the Lancaster, PA Old Order Amish settlement. We focused on variants in 78 genes deemed clinically actionable by the American College of Medical Genetics and Genomics (ACMG) or Geisinger's MyCode Health Initiative. ES revealed 3191 total variants among these genes including 480 nonsynonymous variants. After quality control and filtering, we applied the ACMG/AMP guidelines for variant interpretation and classified seven variants, across seven genes, as either pathogenic or likely pathogenic. Through genetic drift, all seven variants, are highly enriched in the Amish compared to nonfounder populations. In total, 14.7% of Lancaster Amish individuals carry at least one of these variants, largely explained by the 13% who harbor a copy of a single variant in APOB. Other studies report combined frequencies of pathogenic/likely pathogenic (P/LP) variants in actionable genes between 2.0% and 6.2% in outbred populations. The Amish population harbors fewer actionable variants compared to similarly characterized nonfounder populations but have a higher frequency of each variant identified, offering opportunities for efficient and cost‐effective targeted precision medicine.