Diagnostic yield and clinical utility of genetic testing in children with seizure onset after 2 years of age: an update

1525 Background: Genetic testing is a powerful tool for stratifying cancer risk. Multiplex gene panel (MGP) testing allows simultaneous analysis of multiple high- and moderate- penetrance genes. However, the diagnostic yield and clinical utility of panels remain to be further delineated. Methods: A report of a fully accrued trial (N = 2000) of patients undergoing cancer-risk assessment. Patients were enrolled in a multicenter prospective cohort study where diagnostic yield and off-target mutation detection was evaluated of a 25 gene MGP comprised of APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53. Patients were enrolled if they met standard testing guidelines or were predicted to have a ≥2.5% mutation probability by validated models. Differential diagnoses (DDx) were generated after expert clinical genetics assessment, formulating up to 8 inherited cancer syndromes ranked by estimated likelihood. Results: 1998/2000 patients had reported MGP test results. Women constituted 81% of the sample, and 40% were Hispanic; 241 tested positive for at least 1 pathogenic mutation (12.1%) and 689 (34.5%) patients carried at least 1 variant of uncertain significance. The most frequently identified mutations were in BRCA1 (17%, n = 41), BRCA2 (15%, n = 36), APC (8%, n = 19), CHEK2 (7%, n = 17), ATM (7%, n = 16). 39 patients (16%) had at least 1 pathogenic mutation in a mismatch repair (MMR) gene ( MLH1, n = 10; MSH2, n = 10; MSH6, n = 8; PMS2, n = 11). 43 individuals (18%) had MUTYH mutations – 41 were monoallelic. Among 19 patients who had mutations in APC – 16 were APC I1307K. Only 65% (n = 159) of PV results were included in the DDx, with 35% (n = 86) of mutations not clinically suspected. Conclusions: In a diverse cohort, multiplex panel use increased genetic testing yield substantially: 35% carried pathogenic mutations in unsuspected genes, suggesting a significant contribution of expanded multiplex testing to clinical cancer risk assessment. The identification of off-target mutations broadens our understanding of cancer risk and genotype-phenotype correlations. Follow-up is ongoing to assess the clinical utility of multiplex gene panel testing. Clinical trial information: NCT02324062.

Download Full-text

The NYCKidSeq project: study protocol for a randomized controlled trial incorporating genomics into the clinical care of diverse New York City children

10.1101/2020.09.02.20186361 ◽

2020 ◽

Author(s):

Jacqueline A. Odgis ◽

Katie M. Gallagher ◽

Sabrina A. Suckiel ◽

Katherine E. Donohue ◽

Michelle A. Ramos ◽

...

Keyword(s):

Randomized Controlled Trial ◽

Genetic Testing ◽

Clinical Utility ◽

Diagnostic Yield ◽

Controlled Trial ◽

Genomic Medicine ◽

Whole Genome ◽

Diverse Populations ◽

Randomized Controlled ◽

Genomic Results

Background: Increasingly, genomics is informing clinical practice, but challenges remain for medical professionals lacking genetics expertise, and in access to and clinical utility of genomic testing for minority and underrepresented populations. The latter is a particularly pernicious problem due to the historical lack of inclusion of racially and ethnically diverse populations in genomic research and genomic medicine. A further challenge is the rapidly changing landscape of genetic tests, and considerations of cost, interpretation and diagnostic yield for emerging modalities like whole genome sequencing. Methods: The NYCKidSeq project is a randomized controlled trial recruiting 1,130 children and young adults predominantly from Harlem and the Bronx with suspected genetic disorders in three disease categories: neurologic, cardiovascular, and immunologic. Two clinical genetic tests will be performed for each participant, either proband, duo or trio whole-genome sequencing (depending on sample availability) and proband targeted gene panels. Clinical utility, cost and diagnostic yield of both testing modalities will be assessed. This study will evaluate the use of a novel, digital platform (GUÍA) to digitize the return of genomic results experience and improve participant understanding for English- and Spanish-speaking families. Surveys will collect data at three study visits; baseline (0 months), results disclosure visit (ROR1, +3 months), and follow up visit (ROR2, +9 months). Outcomes will assess parental understanding of and attitudes towards receiving genomic results for their child and behavioral, psychological and social impact of results. We will also conduct a pilot study to assess a digital tool called GenomeDiver designed to enhance communication between clinicians and genetic testing labs. We will evaluate GenomeDiver's ability to increase the diagnostic yield compared to standard practices, to improve clinician's ability to perform targeted reverse phenotyping, and to increase the efficiency of genetic testing lab personnel. Discussion: The NYCKidSeq project will contribute to the innovations and best practices in communicating genomic test results to diverse populations. This work will inform strategies for implementing genomic medicine in health systems serving diverse populations using methods that are clinically useful, technologically savvy, culturally sensitive, and ethically sound.

Download Full-text

Clinical Utility of Exome Sequencing and Reinterpreting Genetic Test Results in Children and Adults With Epilepsy

Frontiers in Genetics ◽

10.3389/fgene.2020.591434 ◽

2020 ◽

Vol 11 ◽

Author(s):

Yong-li Jiang ◽

Changgeng Song ◽

Yuanyuan Wang ◽

Jingjing Zhao ◽

Fang Yang ◽

...

Keyword(s):

Genetic Testing ◽

Clinical Utility ◽

Genetic Test ◽

Diagnostic Yield ◽

Clinical Information ◽

Test Results ◽

Diagnostic Potential ◽

Genetic Test Results ◽

Diagnosis Rate ◽

Clinically Significant

The clinical utility of genetic testing for epilepsy has been enhanced with the advancement of next-generation sequencing (NGS) technology along with the rapid updating of publicly available databases. The aim of this study was to evaluate the diagnostic yield of NGS and assess the value of reinterpreting genetic test results in children and adults with epilepsy. We performed genetic testing on 200 patients, including 82 children and 118 adults. The results were classified into three categories: positive, inconclusive, or negative. The reinterpretation of inconclusive results was conducted in April 2020. Overall, we identified disease-causing variants in 12% of the patients in the original analysis, and 14.5% at reinterpretation. The diagnostic yield for adults with epilepsy was similar to that for children (11 vs. 19.5%, p = 0.145). After reinterpretation, 9 of the 86 patients who initially had inconclusive results obtained a clinically significant change in diagnosis. Among these nine revised cases, five obtained positive diagnoses, representing a diagnosis rate of 5.8% (5/86). Manual searches for additional evidence of pathogenicity for candidate variants and updated patient clinical information were the main reasons for diagnostic reclassification. This study emphasizes the diagnostic potential of combining NGS and reinterpretation of inconclusive genetic test reports in children and adults with epilepsy.

Download Full-text

Clinical utility of genetic testing in 201 preschool children with inherited eye disorders

Genetics in Medicine ◽

10.1038/s41436-019-0722-8 ◽

2019 ◽

Vol 22 (4) ◽

pp. 745-751

Author(s):

Eva Lenassi ◽

Jill Clayton-Smith ◽

Sofia Douzgou ◽

Simon C. Ramsden ◽

Stuart Ingram ◽

...

Keyword(s):

Preschool Children ◽

Genetic Testing ◽

Clinical Utility ◽

Diagnostic Yield ◽

Anterior Segment ◽

Ectopia Lentis ◽

Anterior Segment Dysgenesis ◽

Eye Disorders ◽

Retinal Disorders ◽

Inherited Retinal Disorders

Abstract Purpose A key property to consider in all genetic tests is clinical utility, the ability of the test to influence patient management and health outcomes. Here we assess the current clinical utility of genetic testing in diverse pediatric inherited eye disorders (IEDs). Methods Two hundred one unrelated children (0–5 years old) with IEDs were ascertained through the database of the North West Genomic Laboratory Hub, Manchester, UK. The cohort was collected over a 7-year period (2011–2018) and included 74 children with bilateral cataracts, 8 with bilateral ectopia lentis, 28 with bilateral anterior segment dysgenesis, 32 with albinism, and 59 with inherited retinal disorders. All participants underwent panel-based genetic testing. Results The diagnostic yield of genetic testing for the cohort was 64% (ranging from 39% to 91% depending on the condition). The test result led to altered management (including preventing additional investigations or resulting in the introduction of personalized surveillance measures) in 33% of probands (75% for ectopia lentis, 50% for cataracts, 33% for inherited retinal disorders, 7% for anterior segment dysgenesis, 3% for albinism). Conclusion Genetic testing helped identify an etiological diagnosis in the majority of preschool children with IEDs. This prevented additional unnecessary testing and provided the opportunity for anticipatory guidance in significant subsets of patients.

Download Full-text

Multigene Panel Testing in a Large Cohort of Adults With Epilepsy

Neurology Genetics ◽

10.1212/nxg.0000000000000650 ◽

2021 ◽

Vol 8 (1) ◽

pp. e650

Author(s):

Dianalee McKnight ◽

Sara L. Bristow ◽

Rebecca M. Truty ◽

Ana Morales ◽

Molly Stetler ◽

...

Keyword(s):

Genetic Testing ◽

Diagnostic Yield ◽

Specific Treatment ◽

Clinical Information ◽

Cross Sectional Study ◽

Seizure Onset ◽

Adult Care ◽

Pharmacoresistant Epilepsy ◽

Cross Sectional ◽

Diagnostic Finding

Background and ObjectivesAlthough genetic testing among children with epilepsy has demonstrated clinical utility and become a part of routine testing, studies in adults are limited. This study reports the diagnostic yield of genetic testing in adults with epilepsy.MethodsUnrelated individuals aged 18 years and older who underwent diagnostic genetic testing for epilepsy using a comprehensive, next-generation sequencing-based, targeted gene panel (range 89–189 genes) were included in this cross-sectional study. Clinical information, provided at the discretion of the ordering clinician, was reviewed and analyzed. Diagnostic yield was calculated for all individuals including by age at seizure onset and comorbidities based on clinician-reported information. The proportion of individuals with clinically actionable genetic findings, including instances when a specific treatment would be indicated or contraindicated due to a diagnostic finding, was calculated.ResultsAmong 2,008 individuals, a diagnostic finding was returned for 218 adults (10.9%), with clinically actionable findings in 55.5% of diagnoses. The highest diagnostic yield was in adults with seizure onset during infancy (29.6%, 0–1 year), followed by in early childhood (13.6%, 2–4 years), late childhood (7.0%, 5–10 years), adolescence (2.4%, 11–17 years), and adulthood (3.7%, ≥18 years). Comorbid intellectual disability (ID) or developmental delay resulted in a high diagnostic yield (16.0%), most notably for females (19.6% in females vs 12.3% in males). Among individuals with pharmacoresistant epilepsy, 13.5% had a diagnostic finding, and of these, 57.4% were clinically actionable genetic findings.DiscussionThese data reinforce the utility of genetic testing for adults with epilepsy, particularly for those with childhood-onset seizures, ID, and pharmacoresistance. This is an important consideration due to longer survival and the complexity of the transition from pediatric to adult care. In addition, more than half of diagnostic findings in this study were considered clinically actionable, suggesting that genetic testing could have a direct impact on clinical management and outcomes.

Download Full-text

Clinical utility of genetic testing in kidney transplantation

Molecular Genetics and Metabolism ◽

10.1016/s1096-7192(21)00289-4 ◽

2021 ◽

Vol 132 ◽

pp. S134

Author(s):

Lauren Beretich ◽

Sarah McCormick ◽

Trudy McKanna ◽

Hossein Tabriziani ◽

Paul Billings ◽

...

Keyword(s):

Kidney Transplantation ◽

Genetic Testing ◽

Clinical Utility

Download Full-text

Diagnostic Yield and Clinical Utility of Abdominopelvic CT Following Emergent Laparotomy for Trauma

Radiology ◽

10.1148/radiol.2016151946 ◽

2016 ◽

Vol 280 (3) ◽

pp. 735-742 ◽

Cited By ~ 5

Author(s):

Adam K. Haste ◽

Brian L. Brewer ◽

Scott D. Steenburg

Keyword(s):

Clinical Utility ◽

Diagnostic Yield ◽

Abdominopelvic Ct ◽

Emergent Laparotomy

Download Full-text

Abstract 2928: Sudden Arrhythmic Death Syndrome-Diagnostic Yield Of Combined Clinical & Genetic Screening In A British Specialist Clinic

Circulation ◽

10.1161/circ.116.suppl_16.ii_653-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Pier D Lambiase ◽

Juan C Kaski ◽

Eileen Firman ◽

Perry M Elliott ◽

Akbar K Ahmed ◽

...

Keyword(s):

Heart Disease ◽

Genetic Testing ◽

Screening Programme ◽

Diagnostic Yield ◽

Challenge Test ◽

Structural Heart Disease ◽

Clinical Screening ◽

Arrhythmic Death ◽

Sudden Arrhythmic Death Syndrome ◽

Index Cases

Introduction: Sudden arrhythmic death syndrome (SADS) arises through disorders of ion channel function or structural heart disease. It accounts for over 400 deaths in the UK per annum. To date there has been no comprehensive analysis of the diagnostic yield and efficacy of a family screening approach in SADS index cases where the post mortem heart is structurally normal after expert pathological review. Methods: 118 SADS families where the SADS victim died between 1 and 35 years of age were evaluated in a systematic family screening programme between 2003–2006. All SADS index cases had a structurally normal heart after expert review of all available tissue. All studied relatives underwent resting, signal averaged ECG, 24h Holter, exercise ECG with V0 2 max, transthoracic echocardiography and an ajmaline challenge test after initial clinical screening. Systematic mutation analysis was performed on the known long QT (LQT)genes including SCN5A & ryanodine receptor/ARVC genes when clinically suspected. Results: The most common modes of death were rest in 28%, sleep in 25% and exercise in 18%. Clinical screening identified an inherited electrical cause of SADS in 41 of the 118 families (35%)-20 Brugada, 18 LQT Syndrome, 3 Catecholiminergic Polymorphic Ventricular Tachycardia (CPVT). Structural heart disease was identified in 5 ARVC & 2 DCM families. 26 ICDs have been implanted in affected family members-4 LQTS, 7 Brugada, 2 CPVT, 2 ARVC, 2 DCM and 9 on clinical grounds without a definitive diagnosis. The ECG (37%) and ajmaline challenge test (49%) had the highest diagnostic yield in families with a positive diagnosis. To date, genetic testing has increased the diagnostic yield by 5% (6/118 families-2 KCNQ1, 1 HERG, 2 SCN5A, 1 ARVC ), confirming a clinical diagnosis in 6.6%–3 KCNQ1, 3 SCN5A, 1 HERG, 1 KCNH2. Conclusions: Systematic clinical screening in relatives of SADS victims has a diagnostic yield of 35% increasing to 40% with genetic testing. Electrical causes of SADS predominate in these families. These findings demonstrate that a systematic clinical screening programme in SADS families is both achievable and effective. The full impact of gene testing (including RyR mutations) upon diagnostic yield is awaited.

Download Full-text

Genetic testing for color vision deficiency

The EuroBiotech Journal ◽

10.24190/issn2564-615x/2017/s1.10 ◽

2017 ◽

Vol 1 (s1) ◽

pp. 32-34

Author(s):

Andi Abeshi ◽

Alice Bruson ◽

Tommaso Beccari ◽

Munis Dundar ◽

Leonardo Colombo ◽

...

Keyword(s):

Risk Assessment ◽

Genetic Testing ◽

Color Vision ◽

Clinical Utility ◽

Autosomal Dominant ◽

Scientific Literature ◽

Genetic Test ◽

Clinical Findings ◽

Color Vision Deficiency ◽

Dark Adaptometry

Abstract We studied the scientific literature and disease guidelines in order to summarize the clinical utility of genetic testing for color vision deficiency (CVD). Deuteranopia affects 1 in 12 males and is inherited in an X-linked recessive manner. It is associated with variations in the OPN1LW (OMIM gene: 300822; OMIM disease: 303900) and OPN1MW (OMIM gene: 300821; OMIM disease: 303800) genes. Tritanopia has a prevalence of 1 in 10 000, is inherited in an autosomal dominant manner, and is related to variations in the OPN1SW (OMIM gene: 613522; OMIM disease: 190900) gene. Blue cone monochromatism has a prevalence of 1 in 100 000, is inherited in an X-linked recessive manner and is related to mutations in the OPN1LW (OMIM gene: 300822; OMIM disease: 303700) and OPN1MW (OMIM gene: 300821; OMIM disease: 303700) genes. Clinical diagnosis is based on clinical findings, ophthalmogical examination, family history, electroretingraphy, color vision testing and dark adaptometry. The genetic test is useful for confirming diagnosis, and for differential diagnosis, couple risk assessment and access to clinical trials.

Download Full-text