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The Journal of Allergy and Clinical... Oct 2022Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges. (Review)
Review
BACKGROUND
Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges.
OBJECTIVES
This study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health.
METHODS
This study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity.
RESULTS
Probands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9 of 22, 40.9%). One-quarter of the molecular diagnoses (92 of 361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251 of 361 of these molecular diagnoses (69.5%) could translate into ≥1 management option.
CONCLUSIONS
This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale.
Topics: Exome; Female; Genetic Testing; Genomics; Humans; Male; Phenotype; Prospective Studies
PubMed: 35753512
DOI: 10.1016/j.jaci.2022.06.009 -
Annual Review of Medicine Jan 2021Although the explosive growth of direct-to-consumer (DTC) genetic testing has moderated, a substantial number of patients are choosing to undergo genetic testing outside... (Review)
Review
Although the explosive growth of direct-to-consumer (DTC) genetic testing has moderated, a substantial number of patients are choosing to undergo genetic testing outside the purview of their regular healthcare providers. Further, many industry leaders have been expanding reports to cover many more genes, as well as partnering with employers and others to expand access. This review addresses continuing concerns about DTC genetic testing quality, psychosocial impact, integration with medical practice, effects on the healthcare system, and privacy, as well as emerging concerns about third-party interpretation services and non-health-related uses such as investigative genetic genealogy. It concludes with an examination of two possible futures for DTC genetic testing: merger with traditional modes of healthcare delivery or continuation as a parallel system for patient-driven generation of health-relevant information. Each possibility is associated with distinctive questions related to value and risk.
Topics: Direct-To-Consumer Screening and Testing; Genetic Testing; Genetics; Humans; Quality Improvement
PubMed: 32735764
DOI: 10.1146/annurev-med-070119-114727 -
Genome Medicine Jan 2023Rare diseases collectively impose a significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic...
BACKGROUND
Rare diseases collectively impose a significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic diagnostic services and the associated personalized management plans.
METHODS
We established a clinical genomics and genetic counseling facility, within a multidisciplinary tertiary pediatric center, in the United Arab Emirates to locally diagnose and manage patients with rare diseases. Clinical genomic investigations included exome-based sequencing, chromosomal microarrays, and/or targeted testing. We assessed the diagnostic yield and implications for clinical management among this population. Variables were compared using the Fisher exact test. Tests were 2-tailed, and P < .05 was considered statistically significant.
RESULTS
We present data on 1000 patients with rare diseases (46.2% females; average age, 4.6 years) representing 47 countries primarily from the Arabian Peninsula, the Levant, Africa, and Asia. The cumulative diagnostic yield was 32.5% (95% CI, 29.7-35.5%) and was higher for genomic sequencing-based testing than chromosomal microarrays (37.9% versus 17.2%, P = 0.0001) across all indications, consistent with the higher burden of single gene disorders. Of the 221 Mendelian disorders identified in this cohort, the majority (N = 184) were encountered only once, and those with recessive inheritance accounted for ~ 62% of sequencing diagnoses. Of patients with positive genetic findings (N = 325), 67.7% were less than 5 years of age, and 60% were offered modified management and/or intervention plans. Interestingly, 24% of patients with positive genetic findings received delayed diagnoses (average age, 12.4 years; range 7-37 years), most likely due to a lack of access to genomic investigations in this region. One such genetic finding ended a 15-year-long diagnostic odyssey, leading to a life-threatening diagnosis in one patient, who was then successfully treated using an experimental allogenic bone marrow transplant. Finally, we present cases with candidate genes within regions of homozygosity, likely underlying novel recessive disorders.
CONCLUSIONS
Early access to genomic diagnostics for patients with suspected rare disorders in the Middle East is likely to improve clinical outcomes while driving gene discovery in this genetically underrepresented population.
Topics: Child; Child, Preschool; Female; Humans; Male; Exome; Genetic Testing; Genomics; Middle East; Rare Diseases; Adolescent; Young Adult; Adult
PubMed: 36703223
DOI: 10.1186/s13073-023-01157-8 -
Genetics in Medicine : Official Journal... Jan 2021To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected monogenic kidney disease.
PURPOSE
To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected monogenic kidney disease.
METHODS
We performed clinically accredited singleton ES in a prospectively ascertained cohort of 204 patients assessed in multidisciplinary renal genetics clinics at four tertiary hospitals in Melbourne, Australia.
RESULTS
ES identified a molecular diagnosis in 80 (39%) patients, encompassing 35 distinct genetic disorders. Younger age at presentation was independently associated with an ES diagnosis (p < 0.001). Of those diagnosed, 31/80 (39%) had a change in their clinical diagnosis. ES diagnosis was considered to have contributed to management in 47/80 (59%), including negating the need for diagnostic renal biopsy in 10/80 (13%), changing surveillance in 35/80 (44%), and changing the treatment plan in 16/80 (20%). In cases with no change to management in the proband, the ES result had implications for the management of family members in 26/33 (79%). Cascade testing was subsequently offered to 40/80 families (50%).
CONCLUSION
In this pragmatic pediatric and adult cohort with suspected monogenic kidney disease, ES had high diagnostic and clinical utility. Our findings, including predictors of positive diagnosis, can be used to guide clinical practice and health service design.
Topics: Adult; Australia; Child; Exome; Genetic Testing; Humans; Kidney Diseases; Exome Sequencing
PubMed: 32939031
DOI: 10.1038/s41436-020-00963-4 -
Epileptic Disorders : International... Oct 2022Epilepsy genetics is a rapidly developing field, in which novel disease-associated genes, novel mechanisms associated with epilepsy, and precision medicine approaches...
Epilepsy genetics is a rapidly developing field, in which novel disease-associated genes, novel mechanisms associated with epilepsy, and precision medicine approaches are continuously being identified. In the past decade, advances in genomic knowledge and analysis platforms have begun to make clinical genetic testing accessible for, in principle, people of all ages with epilepsy. For this reason, the Genetics Commission of the International League Against Epilepsy (ILAE) presents this update on clinical genetic testing practice, including current techniques, indications, yield of genetic testing, recommendations for pre- and post-test counseling, and follow-up after genetic testing is completed. We acknowledge that the resources vary across different settings but highlight that genetic diagnostic testing for epilepsy should be prioritized when the likelihood of an informative finding is high. Results of genetic testing, in particular the identification of causative genetic variants, are likely to improve individual care. We emphasize the importance of genetic testing for individuals with epilepsy as we enter the era of precision therapy.
Topics: Diagnostic Techniques and Procedures; Epilepsy; Genetic Testing; Humans
PubMed: 35830287
DOI: 10.1684/epd.2022.1448 -
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 -
Revue Medicale Suisse Apr 2024
Topics: Humans; Lung Neoplasms; Early Detection of Cancer; Tomography, X-Ray Computed; Mass Screening; Adult; Practice Guidelines as Topic
PubMed: 38665110
DOI: 10.53738/REVMED.2024.20.871.859 -
American Journal of Clinical Pathology Jul 2019To provide a clinical laboratory perspective on the Verifying Accurate Leading-edge IVCT Development Act (VALID) discussion draft. This potential legislative effort, if... (Review)
Review
OBJECTIVES
To provide a clinical laboratory perspective on the Verifying Accurate Leading-edge IVCT Development Act (VALID) discussion draft. This potential legislative effort, if enacted, would overhaul the regulatory oversight of in vitro diagnostics (IVDs) in the United States and create a single system for regulation of conventional IVDs and laboratory-developed tests (LDTs).
METHODS
A concise literature-based review of LDT regulation is presented followed by a discussion of key concerns pertinent to clinical laboratories that should be considered in future IVD regulatory reform efforts.
RESULTS
Key issues identified include the importance of fostering innovation, preserving patient safety, protecting the practice of laboratory medicine, and minimizing undue regulatory burden. Clinical laboratories are not equivalent to manufacturing facilities and would therefore encounter challenges in implementing device-centric regulatory oversight models.
CONCLUSIONS
It is imperative that a clinical laboratory perspective on LDTs is understood and incorporated prior to advancement of future legislative proposals.
Topics: Clinical Laboratory Services; Diagnostic Tests, Routine; Humans; United States; United States Food and Drug Administration
PubMed: 31242284
DOI: 10.1093/ajcp/aqz096 -
Current Opinion in Pediatrics Dec 2019This review discusses the state of at-home genetic testing, including both direct-to-consumer and consumer-directed genetic testing, for children. (Review)
Review
PURPOSE OF REVIEW
This review discusses the state of at-home genetic testing, including both direct-to-consumer and consumer-directed genetic testing, for children.
RECENT FINDINGS
At-home genetic testing continues to increase in popularity and laboratories are starting to offer tests geared towards newborns and children. Available at-home genetic tests for children address ancestral descent, supplement newborn screening, or provide risks for childhood and adult-onset disorders as well as pharmacogenomic data. However, there are aspects of at-home testing that are unique to children that both providers and parents need to be aware of before considering this type of testing; these include issues related to motivations for testing; privacy concerns; result interpretation; ethical, legal and social implications; and impact on family relationships, among others.
SUMMARY
This review addresses the challenges associated with at-home genetic testing in children and provides guidance for pediatricians and other health care providers who field inquiries about this type of testing or who are presented with at-home genetic test results for interpretation.
Topics: Adult; Child; Direct-To-Consumer Screening and Testing; Genetic Testing; Humans; Infant, Newborn; Neonatal Screening; Parents; Pediatrics
PubMed: 31693579
DOI: 10.1097/MOP.0000000000000824 -
Deutsches Arzteblatt International Feb 2023
Topics: Humans; Infant, Newborn; Neonatal Screening; Hearing; Mass Screening
PubMed: 37005719
DOI: 10.3238/arztebl.m2022.0269