Carrier detection probabilities for autosomal recessive variants in unrelated and consanguineous couples - an evaluation of the 86 genes of the ACMG 'Tier 3' panel

摘要

Carrier screening for autosomal recessive variants has become a cornerstone of community and public health genetics. While the first carrier screening programs were confined to conditions with relatively high prevalence, and hence well-known carrier frequency, the number of candidate genes has increased greatly since the advent of high-throughput DNA sequencing technologies. The epidemiological database of the ensuing gene panels is mostly sparse, and judgement of their performance is, therefore, anything but straightforward. We therefore derived estimates of the carrier detection probabilities among non-consanguineous and consanguineous couples as expected using the 'Tier 3' carrier screening gene panel recently recommended by the American College of Medical Genetics (ACMG). For non-Finnish Europeans, the respective estimate for unrelated couples equals 0.63%, implying that the ACMG Tier 3 panel accounts for over 90% of the genetic load for autosomal recessive diseases in this population. Among the offspring of first cousins, the corresponding incidence is expected to be tenfold higher, an increase still consistent with previous estimates of the overall risk of birth defects for this type of mating. Our considerations are intended to aid the implementation of carrier screening programs and to provide additional support to reproductive counselling and to obtaining informed consent.