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

Abstract

Purpose: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.Methods: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.Results: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.Conclusion: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.

The Israeli national population program of genetic carrier screening for reproductive purposes

“…Much data on the carrier frequency were already available for many of the diseases frequent among the Ashkenazi Jews. 10,[12][13][14] For diseases that are relatively frequent in the other non-Ashkenazi communities, however, this report is the first to outline carrier frequency based on relatively large numbers of screened individuals. In the few instances where the carrier frequency was lower than expected ( Table 1), it was still more than the 1% frequency recommended for screening by the American College of Medical Genetics and Genomics.…”

“…Such an approach has been proposed by several groups and is beginning to be implemented. 10 One problem is that in a sequential screening program such as the one currently implemented in Israel, a universal test will increase the cases in which one individual is found to be a carrier whereas the other partner is from a community in which the disease is rare. This will invariably increase the couple's level of anxiety and lead to additional tests (e.g., sequencing) that are not justified.…”

Targeted mutation screening panels expose systematic population bias in detection of cystic fibrosis risk

“…Carrier screening was performed with four targeted mutation panels: the ACMG-recommended core panel with 23 mutations, 7 the Integrated Genetics CFplus panel with 92 CFTR mutations, 9 the Counsyl Family Prep Screen 1.0 panel with 103 CFTR mutations, 8 and the Recombine CarrierMap panel with 108 CFTR mutations (http://www.recombine.com, accessed on 20 January 2015). In addition, mock screening was performed with the hypothetical targeted mutation panel representing the 159 variants characterized by Sosnay et al 11 in genomes from the CFTR2 patient cohort.…”

“…7 Since the establishment of the core ACMG panel, numerous commercial laboratories have produced expanded genetic panels of 90 or more CFTR variants, including those designed by the genetic testing companies Integrated Genetics, Counsyl, and Recombine. 8,9 Original research article Although DNA genotyping can be extraordinarily accurate from an analytical perspective, it is not sufficient by itself for determination of downstream effects of gene function and prediction of phenotypes in hypothesized homozygous or compound heterozygous individuals (see Cooper et al for a review 10 ). This is especially true for diseases with continuous phenotypes, like CF.…”

Changing trends in carrier screening for genetic disease in the United States

“…Lazarin et al reported on a targeted mutation panel which analyzed 417 disease causing mutations associated with 108 disorders 20. In their cohort of 23, 453 patients of mixed ethnicities, 24% were identified as carriers of at least one mutation.…”