Reflexive standardization and the resolution of uncertainty in the genomics clinic

Abstract

In genomics, the clinical application of Next Generation Sequencing technologies (such as Whole Genome or Exome Sequencing) has attracted considerable attention from UK policymakers, interested in the benefits such technologies could bring the National Health Service. However, this boosterism plays little attention to the challenges raised by a kind of result known as a Variant of Uncertain Significance, or VUS, which require clinical geneticists and related colleagues to classify ambiguous genomic variants as ‘benign’ or ‘pathogenic’. With a rigorous analysis based on data gathered at 290 clinical meetings over a two-year period, this paper presents the first ethnographic account of decision-making around NGS technology in a NHS clinical genomics service, broadening our understanding of the role formal criteria play in the classification of VUS. Drawing on Stefan Timmermans’ concept of ‘reflexive standardisation’ to explore the way in which clinical genetics staff classify such variants this paper explores the application of a set of criteria drafted by the American College of Medical Genetics and Genomics, highlighting the flexible way in which various resources – variant databases, computer programmes, the research literature – are drawn on to reach a decision. A crucial insight is how professionals’ perception of, and trust in, the clinical practice at other genomics centres in the NHS, shapes their own application of criteria and the classification of a VUS as either benign or pathogenic.

In Vitro Modeling as a Tool for Testing Therapeutics for Spinal Muscular Atrophy and IGHMBP2-Related Disorders

“…We obtained a primary cell line from a suspected SMARD1/CMT2S patient who had a compound heterozygous mutation, with one confirmed pathogenic mutation and an additional mutation in the IGHMBP2 gene classified as a variant of uncertain significance (VUS) based on bioinformatic tools at the time of sample acquisition ( Table 4 ). VUS classification and study is important as it can impact patient care and treatment decisions, especially in diseases where treatments are available [ 52 , 53 ]. As the use of genetic testing continues to expand, the accurate classification of VUS becomes increasingly important for patient care and informed decision-making [ 53 ].…”

“…An additional compelling aspect of our in vitro model is its potential to evaluate VUS. In the field of diagnosis, VUS evaluation is critical in determining the significance of mutations and their impact on an individual’s health [ 52 , 53 ], particularly on the IGHMBP2- related disease spectrum, which exhibits variable disease courses and no phenotype-genotype correlation [ 10 , 15 ]. The impact of VUS on disease pathology is even more important in the case of IGHMBP2-related disorders, as there is a potential treatment on the horizon.…”

Taking after a parent: Phenotypic resemblance and the professional familialisation of genomics

“…A crucial driver for this is the way in which different contributory criteria are taken into account when deciding whether a VUS can be classed as pathogenic or not. The decision over a variant's VUS status is the result of 'adding up' different criteria of various strength (for a detailed discussion see Hedgecoe et al, 2023). The way in which such criteria are marshalled and combined means that information about parental phenotype and genotype can serve, in combination, as the 'deciding vote' in these decisions and thus as the key factor in deciding whether a VUS is inherited or has arisen de novo and, therefore, whether or not it can account for the pathology.…”

“…As a VUS, this variant is classed as a '3', sitting in the middle of a five-point scale ranging from Benign (1) and Likely Benign (2) through VUS to Likely Pathogenic (4) and Pathogenic (5). The role of the discussion is to marshal and assess the various available forms of evidence (of differing strength) and combine them to move the classification up into the realms of pathogenic or down to make it benign and thus not relevant for further discussion (For a detailed analysis of this process see Hedgecoe et al, 2023).…”