Variants of uncertain significance in the era of next-generation sequencing

Abstract

Next-generation sequencing (NGS) is now widely used in diagnosing rare diseases. However, it has some limitations, such as variants of uncertain significance (VUS). This can present difficulties even for nurse practitioners involved in clinical genetics. We present three cases from our clinical practice: two targeted panel testing and one exome sequencing. Whole blood samples were collected and sent for NGS analysis. In case 1, a VUS was found in the LITAF gene, which is associated with autosomal dominant Charcot–Marie–Tooth disease type 1C. In case 2, a VUS was reported in the MEFV gene, which is associated with autosomal recessive and autosomal dominant familial Mediterranean fever. In these cases, the reported VUS corresponded to the clinical diagnosis. In case 3, two variants in the heterozygous state were found in the ATP7B gene, which is associated with Wilson disease, and the disorder was later clinically recognized. According to the published guidelines, VUSs should not be discussed as a cause for an observed genetic condition. Nevertheless, if the reported variant is in a gene associated with the clinically diagnosed disorder, and there is a strong genotype-phenotype correlation, it could be suggestive of the etiological role of this variant.

The complementary roles of genome-wide approaches in identifying genes linked to an inherited risk of colorectal cancer

“…However, as with the development of GWAS, the growing application of genome-wide sequencing and the increased amount of available genetic data, has similarly led to increased concerns regarding the utility of this knowledge. Variants of unknown significance (VUS) in known CPGs is one of these problems [ 37 ]. Lucci-Cordisco et al [ 38 ] have reviewed current data regarding VUS of 24 CPGs included by the American College of Medical Genetics/Association for Molecular Pathology in the list of genes that should be considered for the return of incidental findings [ 39 ].…”