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In most medical subspecialties, genetic and genomic testing have become a routine part of clinical care. However, access to genetic testing at the patient, provider, and provincial levels is inequitable, with varying approval processes and public funding and, consequently, differences in access and wait times. Recently, sponsored genetic testing has become more readily available in Canada and is often marketed to practitioners outside of medical genetics who may see advantages in pursuing testing in this way; this has increased availability of genetic testing overall. Here, Bartels et al examine the important ethical, legal, and health care system-related considerations for genetic testing.

SATB2-associated syndrome (SAS) is caused by pathogenic variants in SATB2, which encodes an evolutionarily conserved transcription factor. Despite the broad range of phenotypic manifestations and variable severity related to this syndrome, haploinsufficiency has been assumed to be the primary molecular explanation.In this study, we describe eight individuals with SATB2 variants that affect p.Gly392 (four women, age range 2–16 years; p.Gly392Arg, p.Gly392Glu and p.Gly392Val). Of these, individuals with p.Gly392Arg substitutions were found to have more severe neurodevelopmental phenotypes based on an established rubric scoring system when compared with individuals with p.Gly392Glu, p.Gly392Val and other previously reported causative SATB2 missense variants. Consistent with the observations at the phenotypic level, using human cell-based and model organism functional data, we documented that while all three described p.Gly392 variants affect the same residue and seem to all have a partial loss-of-function effect, some effects on SATB2 protein function appear to be variant-specific. Our results indicate that genotype–phenotype correlations in SAS are more complex than originally thought, and variant-specific genotype–phenotype correlations are needed.

•The Clinician-reported Genetic testing Utility InDEx (C-GUIDE) measures clinical utility.•C-GUIDE has been validated for use in pediatric and adult genetics.•C-GUIDE ratings from two clinicians demonstrate high inter-rater reliability.•Modified instructions will improve rater agreement in future studies.•C-GUIDE aids in addressing the challenge of measuring clinical utility. Advanced genomic and genetic testing technologies are quickly diffusing into clinical practice, but standardized approaches to assessing their clinical utility are limited. Previous work developed and generated preliminary evidence of validity for a novel outcome measure, the Clinician-reported Genetic testing Utility InDEx (C-GUIDE). C-GUIDE is a 17-item measure that captures the utility of genetic testing from the providers’ perspective. Preliminary evidence of its inter-rater reliability was obtained through a clinical vignette study. The purpose of this study was to further assess its inter-rater reliability using actual clinical cases. One genetic counselor and one medical geneticist independently completed C-GUIDE Version 1.1 after genetic test results were disclosed to a shared set of 42 patients. Raters also completed a case description questionnaire, including information about the patient's age, indication for testing, and type of test performed. Inter-rater reliability was assessed by comparing the raters’ C-GUIDE scores using ANOVA to generate intra-class correlation coefficients (ICCs), absolute agreement, and mixed repeated measures ANOVA. Of the 42 patients studied, the most common indications for testing were hearing loss (n = 18) and craniosynostosis (n = 11), and the most common tests ordered were gene panels (n = 20) and microarrays (n = 10). Test results were diagnostic or partially diagnostic for 11 patients, potentially diagnostic for 14 patients, or nondiagnostic for 17 patients. The overall ICC was 0.95 (95% CI, 0.89–0.97) and absolute agreement was acceptable (>70%) for 15 individual items. Inter-rater agreement was excellent (ICC > 0.90) for 8 items, good (ICC = 0.75–0.89) for 3 items, moderate (ICC = 0.50–0.74) for 4 items and poor (ICC < 0.50) for 2 items. Absolute agreement was unacceptable (<70%), and rater agreement was fair (ICC = 0.40–0.59) for 2 items. For the global rating, the ICC was 0.62 (95% CI, 0.39–0.77), and the absolute agreement was 61.9%. Rater instructions for item completion have been modified to improve consistency of item interpretation. Although further assessments of reliability are warranted after modifications, these findings provide additional tentative evidence of C-GUIDE's inter-rater reliability and suggest that it may be useful as a strategy for measuring the value of genetic testing, as perceived by genetics providers.

In this work, we explore whether raw genetic data generated during sequencing ought to be returned to a pediatric patient and/or their parents/guardians. We identify the principles used by various professional societies in their guidelines on the return of secondary findings and apply them to this new context. We conclude that since each situation is unique, decisions should be made on a case-by-case basis according to the best interests of the child.

A Correction to this paper has been published: https://doi.org/10.1038/s41525-021-00191-y