Genetics in Medicine最新文献

Purpose: Exome and genome sequencing (ES, GS) are useful tests to diagnose rare disease in pediatric patients in critical care settings. Genomic test stewardship can increase appropriate use of these tests leading to improved diagnostics and cost savings.

Methods: Mandatory review of ES and GS orders for admitted patients was implemented in March 2023. Outcomes of the reviews, cost analysis, and subsequent test results through February 2024 were analyzed with descriptive statistics.

Results: There were 444 Genetic Test Request (GTR) orders placed for 412 unique patients. Of these, 81 (18.2%) were redirected and 57 (12.8%) required modification after approval leading to an overall cost savings of $345,821.00 USD or $778 USD per order. The combined diagnostic rate was 28.2% in this patient population.

Conclusion: Stewardship of ES/GS orders for pediatric inpatients is an effective tool to improve appropriate usage of these genomic tests. Additional collaboration with stakeholders and expansion of genomic stewardship initiatives may shorten the diagnostic odyssey for critically ill pediatric patients and result in cost savings.

Purpose: Healthcare stakeholders' perspectives on the value of genomic testing vary widely and directly impact the access and practice of genomic medicine. A review of United States healthcare payers' perspectives on genomic testing has not been performed.

Methods: We conducted a systematic literature review of US payers' perspectives on genomic testing in the MEDLINE, PubMed and CINAHL databases. Of the 161 nonduplicate records screened, we summarized findings from 20 included records and using the framework method, common domains were recorded.

Results: Domains included clinical utility, coverage decision frameworks, potential harms, costs, "paying for research," demand/pressure, the flexibility of outcomes considered, and personal utility. There was consensus on the definition of clinical utility as improved health outcomes, and the nuances of genomic testing were reported as challenging to fit within existing coverage decision frameworks. Perspectives varied on accepting broader outcomes or uses of genomic testing and whether costs influence coverage decisions. Study methodologies were heterogeneous.

Conclusion: A deeper understanding of how payers approach genomic testing may allow comparison to other stakeholders' perspectives and may identify challenges, opportunities, and solutions to align a conceptual and evidentiary framework better to demonstrate the value of genomic testing.

Purpose: Families of children in pediatric acute care offered ultra-rapid genomic sequencing are making complex decisions in a high stress period. To reduce complexity for families and clinicians, we offered genomic screening for the child and parents after completion of diagnostic testing. We evaluated uptake, understanding and service delivery preferences.

Methods: A cohort of 235 families who had completed ultra-rapid diagnostic genomic sequencing at 17 Australian hospitals were offered up to three screens on their genomic data: pediatric-onset, adult-onset, expanded couple carrier screening. We investigated decision-making, understanding and service delivery preferences using surveys at three timepoints (pre-counseling, post-counseling, post-result) and performed inductive content analysis of pre-test genetic counseling transcripts.

Results: 119 families (51%) attended genetic counseling with 115 (49%) accepting genomic screening. Survey respondents were more likely to find decisions about couple carrier screening 'easy' (87%) than adult (68%; p=0.002) or pediatric (71%; p=0.01) screening decisions. All respondents with newly detected pathogenic variants accurately recalled this one month later. A delayed offer of screening was acceptable to most respondents (78%).

Conclusion: Separating genomic screening from the stressful diagnostic period is supported by families who demonstrate good knowledge and recall. Our results suggest delaying genomic screening should be trialed more widely.

Introduction: Heterozygous pathogenic variants in NTRK2 (HGNC: 8032) have been associated with global developmental delay. However, only scattered cases have been described in small or general studies. The aim of our work was to consolidate our understanding of NTRK2-related disorders and to delineate the clinical presentation METHODS: We report extended cohort of 44 affected individuals, of whom 19 are from the literature and 25 were previously unreported.

Results: Our analysis led to splitting the cohort into two entities.

Discussion: One group had variants in the cholesterol binding motif of the transmembrane domain, with most of these being the recurrent variant c.1301A>G p.(Tyr434Cys). These variants probably lead to upregulation of TRKB activity and to a severe phenotype of developmental delay/intellectual disability, muscular hypotonia, therapy-refractory epilepsy, visual impairment and blindness, and feeding difficulties. The second group had truncating variants or variants that presumably disturb the 3D structure of the protein leading to loss of function. These individuals had a remarkably milder phenotype of developmental delay, obesity and hyperphagia.

Background: Practice is shifting toward genome-first approaches, such as opportunistic screening for secondary findings (SFs). Analysis of SFs could be extended beyond medically actionable results to include non-medically actionable monogenic disease risks, carrier status, pharmacogenomic variants, and risk variants for common complex disease. However, evidence on the clinical utility of returning these results is lacking. We assessed the outcomes of opportunistic screening for a broad spectrum of SFs by evaluating the yield, impact on clinical management, and consistency between SFs and participants' clinical features and family history.

Methods: Adult cancer patients had GS with the option to learn multiple categories of SFs. Outcomes data were collected through chart review and participant-reported measures up to one year after return of results.

Results: All participants (n=139, 85.6% female, average 54.6 years old) who elected to learn SFs had ≥1 variant reported (100% [139/139]). The yield of reportable findings was highest for pharmacogenomic variants (97.8% [135/138] of participants), followed by common disease risk variants (89.4% [118/132]), carrier status (89.3% [117/131]), and variants related to Mendelian (27.2% [34/125]), medically actionable (15.2% [21/138]), and early-onset neurodegenerative (2.6% [3/117]) disease risks. SFs from the ACMG list (v3.2, non-cancer genes) were reported in 1.4% (2/138) of participants. SFs across all categories demonstrated clinical utility by prompting management changes in 28.1% (39/139) of participants. Moreover, a considerable proportion of participants had suggestive clinical features (49.0% (24/49)]) or family history (21.8% (27/124)) potentially related to their SFs.

Conclusions: Our findings indicate there are potential benefits from opportunistic screening for a broad range of SFs.

Measurement of lysosomal disease (LD) biomarkers can reveal valuable information about disease status. Lyso-globotriaosylceramide (lyso-Gb₃), glucosylsphingosine (lyso-Gb₁), galactosylsphingosine (psychosine), and glucose tetrasaccharide (Glca1-6Glca1-4Glca1-4Glc, Glc₄) are biomarkers associated with Fabry, Gaucher, Krabbe, and Pompe disease, respectively. Clinical biomarker testing is performed to guide patient management, including monitoring disease progression and initiating treatment, and in diagnostic evaluations of either symptomatic patients or asymptomatic individuals with a positive family history or abnormal newborn screen. Biomarker analysis can be performed through independent analysis of a single analyte or as a multiplex assay measuring analytes for more than one disorder utilizing liquid chromatographic separation and tandem mass spectrometric detection. These guidelines were developed to provide technical standards for biomarker analysis, results interpretation, and results reporting, highlighting Fabry, Gaucher, Krabbe, and Pompe diseases as examples.