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Current Opinion in Pediatrics Feb 2024Primary immunodeficiency diseases (PIDs), also called inborn errors of immunity (IEI), are genetic disorders characterized by increased susceptibility to infection... (Review)
Review
PURPOSE OF REVIEW
Primary immunodeficiency diseases (PIDs), also called inborn errors of immunity (IEI), are genetic disorders characterized by increased susceptibility to infection and/or aberrant regulation of immunological pathways. This review summarizes and highlights the new IEI disorders in the International Union of Immunological Societies (IUIS) 2022 report and current trends among new PIDs.
RECENT FINDINGS
Since the 2019 IUIS report and the 2021 IUIS interim update, the IUIS IEI classification now includes 485 validated IEIs. Increasing utilization of genetic testing and advances in the strategic evaluation of genetic variants has continued to drive the identification of, not only novel IEI disorders, but additional genetic etiologies for known IEI disorders and phenotypes.
SUMMARY
The recognition of new IEIs continues to advance at a rapid pace, which is due in part to increased performance and application of genetic modalities as well as expansion of the underlying science that is applied to convincingly establish causality. These disorders, as a whole, continue to emphasize the specificity of immunity, complexity of immune mechanisms, and the fine balance that defines immune homeostasis.
Topics: Humans; Genetic Testing; Homeostasis; Phenotype
PubMed: 38001560
DOI: 10.1097/MOP.0000000000001315 -
JAMA Jul 2023Genomic testing in infancy guides medical decisions and can improve health outcomes. However, it is unclear whether genomic sequencing or a targeted neonatal... (Comparative Study)
Comparative Study
IMPORTANCE
Genomic testing in infancy guides medical decisions and can improve health outcomes. However, it is unclear whether genomic sequencing or a targeted neonatal gene-sequencing test provides comparable molecular diagnostic yields and times to return of results.
OBJECTIVE
To compare outcomes of genomic sequencing with those of a targeted neonatal gene-sequencing test.
DESIGN, SETTING, AND PARTICIPANTS
The Genomic Medicine for Ill Neonates and Infants (GEMINI) study was a prospective, comparative, multicenter study of 400 hospitalized infants younger than 1 year of age (proband) and their parents, when available, suspected of having a genetic disorder. The study was conducted at 6 US hospitals from June 2019 to November 2021.
EXPOSURE
Enrolled participants underwent simultaneous testing with genomic sequencing and a targeted neonatal gene-sequencing test. Each laboratory performed an independent interpretation of variants guided by knowledge of the patient's phenotype and returned results to the clinical care team. Change in clinical management, therapies offered, and redirection of care was provided to families based on genetic findings from either platform.
MAIN OUTCOMES AND MEASURES
Primary end points were molecular diagnostic yield (participants with ≥1 pathogenic variant or variant of unknown significance), time to return of results, and clinical utility (changes in patient care).
RESULTS
A molecular diagnostic variant was identified in 51% of participants (n = 204; 297 variants identified with 134 being novel). Molecular diagnostic yield of genomic sequencing was 49% (95% CI, 44%-54%) vs 27% (95% CI, 23%-32%) with the targeted gene-sequencing test. Genomic sequencing did not report 19 variants found by the targeted neonatal gene-sequencing test; the targeted gene-sequencing test did not report 164 variants identified by genomic sequencing as diagnostic. Variants unidentified by the targeted genomic-sequencing test included structural variants longer than 1 kilobase (25.1%) and genes excluded from the test (24.6%) (McNemar odds ratio, 8.6 [95% CI, 5.4-14.7]). Variant interpretation by laboratories differed by 43%. Median time to return of results was 6.1 days for genomic sequencing and 4.2 days for the targeted genomic-sequencing test; for urgent cases (n = 107) the time was 3.3 days for genomic sequencing and 4.0 days for the targeted gene-sequencing test. Changes in clinical care affected 19% of participants, and 76% of clinicians viewed genomic testing as useful or very useful in clinical decision-making, irrespective of a diagnosis.
CONCLUSIONS AND RELEVANCE
The molecular diagnostic yield for genomic sequencing was higher than a targeted neonatal gene-sequencing test, but the time to return of routine results was slower. Interlaboratory variant interpretation contributes to differences in molecular diagnostic yield and may have important consequences for clinical management.
Topics: Clinical Decision-Making; Genetic Profile; Genomics; Prospective Studies; Whole Genome Sequencing; Genetic Testing; Genetic Diseases, Inborn; Humans; Infant, Newborn; Neonatal Screening; Infant; Sequence Analysis, DNA; Mutation
PubMed: 37432431
DOI: 10.1001/jama.2023.9350 -
The Lancet. Child & Adolescent Health Jul 2023Congenital heart disease (CHD), a wide spectrum of diseases with varied outcomes, is the most common congenital malformation worldwide. In this Series of three papers,... (Review)
Review
Congenital heart disease (CHD), a wide spectrum of diseases with varied outcomes, is the most common congenital malformation worldwide. In this Series of three papers, we describe the burden of CHD in China; the development of screening, diagnosis, treatment, and follow-up strategies; and challenges associated with the disease. We also propose solutions and recommendations for policies and actions to improve the outcomes of CHD. In the first paper in this Series, we focus on prenatal and neonatal screening, diagnosis, and management of CHD. Based on advanced international knowledge, the Chinese Government has developed a network system comprising prenatal screening, diagnosis of CHD subtypes, specialist consultation appointments, and treatment centres for CHD. A new professional discipline, fetal cardiology, has been formed and rapidly developed. Consequently, the overall coverage of prenatal and neonatal screening and the accuracy of CHD diagnoses have gradually improved, and the neonatal CHD mortality rate has decreased substantially. However, China still faces several challenges in the prevention and treatment of CHD, such as insufficient diagnostic capabilities and unqualified consultation services in some regions and rural areas. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Topics: Pregnancy; Infant, Newborn; Female; Humans; Neonatal Screening; Ultrasonography, Prenatal; Heart Defects, Congenital; Prenatal Diagnosis; China
PubMed: 37301215
DOI: 10.1016/S2352-4642(23)00051-2 -
Noninvasive Prenatal Testing Using Circulating DNA and RNA: Advances, Challenges, and Possibilities.Annual Review of Biomedical Data Science Aug 2023Prenatal screening using sequencing of circulating cell-free DNA has transformed obstetric care over the past decade and significantly reduced the number of invasive... (Review)
Review
Prenatal screening using sequencing of circulating cell-free DNA has transformed obstetric care over the past decade and significantly reduced the number of invasive diagnostic procedures like amniocentesis for genetic disorders. Nonetheless, emergency care remains the only option for complications like preeclampsia and preterm birth, two of the most prevalent obstetrical syndromes. Advances in noninvasive prenatal testing expand the scope of precision medicine in obstetric care. In this review, we discuss advances, challenges, and possibilities toward the goal of providing proactive, personalized prenatal care. The highlighted advances focus mainly on cell-free nucleic acids; however, we also review research that uses signals from metabolomics, proteomics, intact cells, and the microbiome. We discuss ethical challenges in providing care. Finally, we look to future possibilities, including redefining disease taxonomy and moving from biomarker correlation to biological causation.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Noninvasive Prenatal Testing; Genetic Testing; Aneuploidy; Cell-Free Nucleic Acids; RNA; Premature Birth
PubMed: 37196360
DOI: 10.1146/annurev-biodatasci-020722-094144 -
International Journal of Molecular... Jul 2023Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal recessive inheritance. The first cases of SMA were reported by Werdnig in 1891. Although the... (Review)
Review
Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal recessive inheritance. The first cases of SMA were reported by Werdnig in 1891. Although the phenotypic variation of SMA led to controversy regarding the clinical entity of the disease, the genetic homogeneity of SMA was proved in 1990. Five years later, in 1995, the gene responsible for SMA, , was identified. Genetic testing of has enabled precise epidemiological studies, revealing that SMA occurs in 1 of 10,000 to 20,000 live births and that more than 95% of affected patients are homozygous for deletion. In 2016, nusinersen was the first drug approved for treatment of SMA in the United States. Two other drugs were subsequently approved: onasemnogene abeparvovec and risdiplam. Clinical trials with these drugs targeting patients with pre-symptomatic SMA (those who were diagnosed by genetic testing but showed no symptoms) revealed that such patients could achieve the milestones of independent sitting and/or walking. Following the great success of these trials, population-based newborn screening programs for SMA (more precisely, -deleted SMA) have been increasingly implemented worldwide. Early detection by newborn screening and early treatment with new drugs are expected to soon become the standards in the field of SMA.
Topics: Infant, Newborn; Humans; Muscular Atrophy, Spinal; Genetic Testing; Homozygote; Neonatal Screening; Inheritance Patterns
PubMed: 37569314
DOI: 10.3390/ijms241511939 -
Current Protocols Aug 2023Analytical method validation provides a means to ensure that data are credible and reproducible. This article will provide a brief introduction to analytical method...
Analytical method validation provides a means to ensure that data are credible and reproducible. This article will provide a brief introduction to analytical method validation as applied to cellular analysis by flow cytometry, along with practical procedures for four different types of validation. The first, Basic Protocol 1 (the limited validation protocol), is recommended for research and non-regulated laboratories. Next, Basic Protocol 2) presents a reasonable, fit-for-purpose validation approach appropriate for biopharma and research settings. Basic Protocol 3 addresses the type of validation performed in clinical laboratories for moderate-risk tests developed in house. Finally, Basic Protocol 4 describes the process that should be applied whenever a method is being transferred from one facility to another. All four validation plans follow the fit-for-purpose validation approach, in which the validation parameters are selected based on the intended use of the assay. These validation protocols represent the minimal requirement and may not be applicable for every intended use such as high-risk clinical assays or data to be used as a primary endpoint in a clinical trial. The recommendations presented here are consistent with the white papers published by the American Association of Pharmaceutical Scientists and the International Clinical Cytometry Society, as well as with Clinical Laboratory Standards Institute Guideline H62: Validation of Assays Performed by Flow Cytometry (CLSI, 2021). © 2023 Wiley Periodicals LLC. Basic Protocol 1: Limited validation Basic Protocol 2: Fit-for-purpose validation for biopharma and research settings Basic Protocol 3: Validation for moderate clinical risk laboratory developed tests Basic Protocol 4: Transfer validation.
Topics: Flow Cytometry; Research Design; Academies and Institutes; Biological Assay; Clinical Laboratory Services
PubMed: 37606503
DOI: 10.1002/cpz1.868 -
American Journal of Human Genetics Jan 2024In 2020, the National Human Genome Research Institute (NHGRI) made ten "bold predictions," including that "the clinical relevance of all encountered genomic variants... (Review)
Review
In 2020, the National Human Genome Research Institute (NHGRI) made ten "bold predictions," including that "the clinical relevance of all encountered genomic variants will be readily predictable, rendering the diagnostic designation 'variant of uncertain significance (VUS)' obsolete." We discuss the prospects for this prediction, arguing that many, if not most, VUS in coding regions will be resolved by 2030. We outline a confluence of recent changes making this possible, especially advances in the standards for variant classification that better leverage diverse types of evidence, improvements in computational variant effect predictor performance, scalable multiplexed assays of variant effect capable of saturating the genome, and data-sharing efforts that will maximize the information gained from each new individual sequenced and variant interpreted. We suggest that clinicians and researchers can realize a future where VUSs have largely been eliminated, in line with the NHGRI's bold prediction. The length of time taken to reach this future, and thus whether we are able to achieve the goal of largely eliminating VUSs by 2030, is largely a consequence of the choices made now and in the next few years. We believe that investing in eliminating VUSs is worthwhile, since their predominance remains one of the biggest challenges to precision genomic medicine.
Topics: Humans; Genetic Variation; Genomics; Precision Medicine; Genetic Testing
PubMed: 38086381
DOI: 10.1016/j.ajhg.2023.11.005 -
Genetics in Medicine : Official Journal... Dec 2023Variants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream...
PURPOSE
Variants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream costs, including time investment by clinicians. We investigated the rate of VUS reported on diagnostic testing via multi-gene panels (MGPs) and exome and genome sequencing (ES/GS) to measure the magnitude of uncertain results and explore ways to reduce their potentially detrimental impact.
METHODS
Rates of inconclusive results due to VUS were collected from over 1.5 million sequencing test results from 19 clinical laboratories in North America from 2020 to 2021.
RESULTS
We found a lower rate of inconclusive test results due to VUSs from ES/GS (22.5%) compared with MGPs (32.6%; P < .0001). For MGPs, the rate of inconclusive results correlated with panel size. The use of trios reduced inconclusive rates (18.9% vs 27.6%; P < .0001), whereas the use of GS compared with ES had no impact (22.2% vs 22.6%; P = ns).
CONCLUSION
The high rate of VUS observed in diagnostic MGP testing warrants examining current variant reporting practices. We propose several approaches to reduce reported VUS rates, while directing clinician resources toward important VUS follow-up.
Topics: Humans; Genetic Predisposition to Disease; Genetic Testing; Genomics; Exome; North America
PubMed: 37534744
DOI: 10.1016/j.gim.2023.100947 -
Annals of Internal Medicine Sep 2023Overdiagnosis is increasingly recognized as a harm of breast cancer screening, particularly for older women.
BACKGROUND
Overdiagnosis is increasingly recognized as a harm of breast cancer screening, particularly for older women.
OBJECTIVE
To estimate overdiagnosis associated with breast cancer screening among older women by age.
DESIGN
Retrospective cohort study comparing the cumulative incidence of breast cancer among older women who continued screening in the next interval with those who did not. Analyses used competing risk models, stratified by age.
SETTING
Fee-for-service Medicare claims, linked to the SEER (Surveillance, Epidemiology, and End Results) program.
PATIENTS
Women 70 years and older who had been recently screened.
MEASUREMENTS
Breast cancer diagnoses and breast cancer death for up to 15 years of follow-up.
RESULTS
This study included 54 635 women. Among women aged 70 to 74 years, the adjusted cumulative incidence of breast cancer was 6.1 cases (95% CI, 5.7 to 6.4) per 100 screened women versus 4.2 cases (CI, 3.5 to 5.0) per 100 unscreened women. An estimated 31% of breast cancer among screened women were potentially overdiagnosed. For women aged 75 to 84 years, cumulative incidence was 4.9 (CI, 4.6 to 5.2) per 100 screened women versus 2.6 (CI, 2.2 to 3.0) per 100 unscreened women, with 47% of cases potentially overdiagnosed. For women aged 85 and older, the cumulative incidence was 2.8 (CI, 2.3 to 3.4) among screened women versus 1.3 (CI, 0.9 to 1.9) among those not, with up to 54% overdiagnosis. We did not see statistically significant reductions in breast cancer-specific death associated with screening.
LIMITATIONS
This study was designed to estimate overdiagnosis, limiting our ability to draw conclusions on all benefits and harms of screening. Unmeasured differences in risk for breast cancer and differential competing mortality between screened and unscreened women may confound results. Results were sensitive to model specifications and definition of a screening mammogram.
CONCLUSION
Continued breast cancer screening was associated with greater incidence of breast cancer, suggesting overdiagnosis may be common among older women who are diagnosed with breast cancer after screening. Whether harms of overdiagnosis are balanced by benefits and for whom remains an important question.
PRIMARY FUNDING SOURCE
National Cancer Institute.
Topics: Aged; Female; Humans; United States; Breast Neoplasms; Mammography; Overdiagnosis; Retrospective Studies; Early Detection of Cancer; Medicare; Mass Screening
PubMed: 37549389
DOI: 10.7326/M23-0133 -
American Journal of Human Genetics Jul 2023Newborn genomic sequencing (NBSeq) to screen for medically important genetic information is of considerable interest but data characterizing the actionability of such...
Newborn genomic sequencing (NBSeq) to screen for medically important genetic information is of considerable interest but data characterizing the actionability of such findings, and the downstream medical efforts in response to discovery of unanticipated genetic risk variants, are lacking. From a clinical trial of comprehensive exome sequencing in 127 apparently healthy infants and 32 infants in intensive care, we previously identified 17 infants (10.7%) with unanticipated monogenic disease risks (uMDRs). In this analysis, we assessed actionability for each of these uMDRs with a modified ClinGen actionability semiquantitative metric (CASQM) and created radar plots representing degrees of penetrance of the condition, severity of the condition, effectiveness of intervention, and tolerability of intervention. In addition, we followed each of these infants for 3-5 years after disclosure and tracked the medical actions prompted by these findings. All 17 uMDR findings were scored as moderately or highly actionable on the CASQM (mean 9, range: 7-11 on a 0-12 scale) and several distinctive visual patterns emerged on the radar plots. In three infants, uMDRs revealed unsuspected genetic etiologies for existing phenotypes, and in the remaining 14 infants, uMDRs provided risk stratification for future medical surveillance. In 13 infants, uMDRs prompted screening for at-risk family members, three of whom underwent cancer-risk-reducing surgeries. Although assessments of clinical utility and cost-effectiveness will require larger datasets, these findings suggest that large-scale comprehensive sequencing of newborns will reveal numerous actionable uMDRs and precipitate substantial, and in some cases lifesaving, downstream medical care in newborns and their family members.
Topics: Humans; Infant, Newborn; Genetic Testing; Genome, Human; Neonatal Screening; Genomics; Exome Sequencing
PubMed: 37279760
DOI: 10.1016/j.ajhg.2023.05.007