An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals

TLDR

Recent advances in genomics have enabled expanded carrier screening panels that assess hundreds of causal mutations, allowing simultaneous measurement of carrier frequencies for many diseases. The study aimed to assess the accuracy of rank‑ordering carrier frequencies, a key factor in designing and prioritizing screening programs, by analyzing data from 23,453 individuals referred for routine recessive disease carrier screening. Multiplex carrier screening was performed on these individuals and the results were aggregated, revealing that 24 % carried at least one of 108 disorders and 5.2 % carried multiple disorders. The analysis provides the most accurate carrier frequency estimates to date for 108 recessive disorders across diverse ethnic groups and supports a pan‑ethnic screening approach that minimizes the use of racial categories.

Abstract

Recent developments in genomics have led to expanded carrier screening panels capable of assessing hundreds of causal mutations for genetic disease. This new technology enables simultaneous measurement of carrier frequencies for many diseases. As the resultant rank-ordering of carrier frequencies impacts the design and prioritization of screening programs, the accuracy of this ranking is a public health concern.A total of 23,453 individuals from many obstetric, genetics, and infertility clinics were referred for routine recessive disease carrier screening. Multiplex carrier screening was performed and results were aggregated for this study.Twenty-four percent of individuals were identified as carriers for at least one of 108 disorders, and 5.2% were carriers for multiple disorders. We report tabulations of carrier frequency by self-identified ethnicity and disease.To our knowledge, this study of a large, ethnically diverse clinical sample provides the most accurate measurements to date of carrier frequencies for hundreds of recessive alleles. The study also yields information on the clinical considerations associated with routine use of expanded panels and provides support for a pan-ethnic screening paradigm that minimizes the use of "racial" categories by the physician, as recommended by recent guidelines.