NGS testing for cardiomyopathy: Utility of adding RASopathy-associated genes.
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ABSTRACT:
SUBMITTER: Ceyhan-Birsoy O
PROVIDER: S-EPMC8191452 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundRASopathies are a group of disorders caused by disruptions to the RAS-MAPK pathway. Despite being in the same pathway, Neurofibromatosis Type 1 (NF1) and Legius syndrome (LS) typically present with phenotypes distinct from Noonan spectrum disorders (NSDs). However, some NF1/LS individuals also exhibit NSD phenotypes, often referred to as Neurofibromatosis-Noonan syndrome (NFNS), and may be mistakenly evaluated for NSDs, delaying diagnosis, and affecting patient management.MethodsA derivation cohort of 28 patients with a prior negative NSD panel and either NFNS or a suspicion of NSD and café-au-lait spots underwent NF1 and SPRED1 sequencing. To further determine the utility and burden of adding these genes, a validation cohort of 505 patients with a suspected RASopathy were tested on a 14-gene RASopathy-associated panel.ResultsIn the derivation cohort, six (21%) patients had disease-causing NF1 or SPRED1 variants. In the validation cohort, 11 (2%) patients had disease-causing variants and 15 (3%) had variants of uncertain significance in NF1 or SPRED1. Of those with disease-causing variants, 5/17 only had an NSD diagnosis.ConclusionsAdding NF1 and SPRED1 to RASopathy panels can speed diagnosis and improve patient management, without significantly increasing the burden of inconclusive results.
| S-EPMC7196473 | biostudies-literature
Project description:BackgroundSomatic genetic testing is rapidly becoming the standard of care in many adult and pediatric cancers. Previously, the standard approach was single-gene or focused multigene testing, but many centers have moved towards broad-based next-generation sequencing (NGS) panels. Here, we report the laboratory validation and clinical utility of a large cohort of clinical NGS somatic sequencing results in diagnosis, prognosis, and treatment of a wide range of pediatric cancers.MethodsSubjects were accrued retrospectively at a single pediatric quaternary-care hospital. Sequence analyses were performed on 367 pediatric cancer samples using custom-designed NGS panels over a 15-month period. Cases were profiled for mutations, copy number variations, and fusions identified through sequencing, and their clinical impact on diagnosis, prognosis, and therapy was assessed.ResultsNGS panel testing was incorporated meaningfully into clinical care in 88.7% of leukemia/lymphomas, 90.6% of central nervous system (CNS) tumors, and 62.6% of non-CNS solid tumors included in this cohort. A change in diagnosis as a result of testing occurred in 3.3% of cases. Additionally, 19.4% of all patients had variants requiring further evaluation for potential germline alteration.ConclusionsUse of somatic NGS panel testing resulted in a significant impact on clinical care, including diagnosis, prognosis, and treatment planning in 78.7% of pediatric patients tested in our institution. Somatic NGS tumor testing should be implemented as part of the routine diagnostic workup of newly diagnosed and relapsed pediatric cancer patients.
| S-EPMC6537185 | biostudies-literature
Project description:Multifocal atrial tachycardia (MAT) has a well-known association with Costello syndrome, but is rarely described with related RAS/MAPK pathway disorders (RASopathies). We report 11 patients with RASopathies (Costello, Noonan, and Noonan syndrome with multiple lentigines [formerly LEOPARD syndrome]) and nonreentrant atrial tachycardias (MAT and ectopic atrial tachycardia) demonstrating overlap in cardiac arrhythmia phenotype. Similar overlap is seen in RASopathies with respect to skeletal, musculoskeletal and cutaneous abnormalities, dysmorphic facial features, and neurodevelopmental deficits. Nonreentrant atrial tachycardias may cause cardiac compromise if sinus rhythm is not restored expeditiously. Typical first-line supraventricular tachycardia anti-arrhythmics (propranolol and digoxin) were generally not effective in restoring or maintaining sinus rhythm in this cohort, while flecainide or amiodarone alone or in concert with propranolol were effective anti-arrhythmic agents for acute and chronic use. Atrial tachycardia resolved in all patients. However, a 4-month-old boy from the cohort was found asystolic (with concurrent cellulitis) and a second patient underwent cardiac transplant for heart failure complicated by recalcitrant atrial arrhythmia. While propranolol alone frequently failed to convert or maintain sinus rhythm, fleccainide or amiodarone, occasionally in combination with propranolol, was effective for RASopathy patient treatment for nonreentrant atrial arrhythmia. Our analysis shows that RASopathy patients may have nonreentrant atrial tachycardia with and without associated cardiac hypertrophy. While nonreentrant arrhythmia has been traditionally associated with Costello syndrome, this work provides an expanded view of RASopathy cardiac arrhythmia phenotype as we demonstrate mutant proteins throughout this signaling pathway can also give rise to ectopic and/or MAT.
| S-EPMC6107379 | biostudies-literature
Project description:BackgroundStress-induced cardiomyopathy (SIC) is a poorly understood condition associated with periods of emotional and physical stress. The clinical approaches for management of SIC are supportive and reactive to patient symptoms.ObjectiveTo utilize next-generation exome sequencing to define genetic variation associated with, and potentially responsible for, this disease.MethodsWe performed exome sequencing of 7 white female patients with SIC. Filtering of the identified variants was performed to limit our investigation to those sequences that passed quality control criteria, were rare or novel, were determined algorithmically to have high impact on the associated protein, and were within regions of high species conservation. All variants were verified by using Sanger sequencing.ResultsExome-sequencing analysis revealed that each patient carried predicted deleterious variants affecting known cardiomyopathy genes. In each case, the identified variant was either not previously found in public human genome data or was previously annotated in a database of clinical variants associated with cardiac dysfunction.ConclusionPatients with SIC harbor deleterious mutations in established cardiomyopathy genes at a level higher than healthy controls. We hypothesize that patients at highest risk for SIC likely live in a compensated state of cardiac dysfunction that manifests clinically only after the myocardium is stressed. In short, we propose that SIC is another example of an occult cardiomyopathy with a distinct physiological trigger and suggest that alternative clinical approaches to these patients may be warranted.AbbreviationsCADD, Combined Annotation Dependent DepletionFPKM, fragments per kilobase pair of exon per million fragments mappedNHLBI GO ESP, National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing ProjectPCR, polymerase chain reactionSIC, stress-induced cardiomyopathy.
| S-EPMC4871739 | biostudies-literature
Project description:DNA analysis by NGS has become important to direct the clinical care of cancer patients. However, NGS is not successful in all cases, and the factors responsible for test failures have not been systematically evaluated.A series of 1528 solid and hematolymphoid tumor specimens was tested by an NGS comprehensive cancer panel during 2012-2014. DNA was extracted and 2×101 bp paired-end sequence reads were generated on cancer-related genes utilizing Illumina HiSeq and MiSeq platforms.Testing was unsuccessful in 343 (22.5%) specimens. The failure was due to insufficient tissue (INST) in 223/343 (65%) cases, insufficient DNA (INS-DNA) in 99/343 (28.9%) cases, and failed library (FL) in 21/343 (6.1%) cases. 87/99 (88%) of the INS-DNA cases had below 10 ng DNA available for testing. Factors associated with INST and INS-DNA failures were site of biopsy (SOB) and type of biopsy (TOB) (both p < 0.0001), and clinical setting of biopsy (CSB, initial diagnosis or recurrence) (p < 0.0001). Factors common to INST and FL were age of specimen (p ≤ 0.006) and tumor viability (p ≤ 0.05). Factors common to INS-DNA and FL were DNA purity and DNA degradation (all p ≤ 0.005). In multivariate analysis, common predictors for INST and INS-DNA included CSB (p = 0.048 and p < 0.0001) and TOB (both p ≤ 0.003), respectively. SOB (p = 0.004) and number of cores (p = 0.001) were specific for INS-DNA, whereas TOB and DNA degradation were associated with FL (p = 0.04 and 0.02, respectively).Pre-analytical causes (INST and INS-DNA) accounted for about 90% of all failed cases; independent of test design. Clinical setting; site and type of biopsy; and number of cores used for testing all correlated with failure. Accounting for these factors at the time of tissue biopsy acquisition could improve the analytic success rate.
| S-EPMC5528718 | biostudies-other
Project description:BACKGROUND:Danon disease (OMIM 300257) is an X-linked lysosomal storage disorder, characterized by hypertrophic cardiomyopathy (HCM), skeletal myopathy, variable intellectual disability, and other minor clinical features. This condition accounts for ~ 4% of HCM patients, with a more severe and early onset phenotype in males, causing sudden cardiac death (SCD) in the first three decades of life. Genetic alterations in the LAMP2 gene are the main cause of this inherited fatal condition. Up to date, more than 100 different pathogenic variants have been reported in the literature. However, the majority of cases are misdiagnosed as HCM or have a delay in the diagnosis. CASE PRESENTATION:Here, we describe a young boy with an early diagnosis of HCM. After 2 episodes of ventricular fibrillation within 2 years, genetic testing identified a novel LAMP2 pathogenic variant. Subsequently, further clinical evaluations showing muscle weakness and mild intellectual disability confirmed the diagnosis of Danon disease. CONCLUSIONS:This report highlights the role of genetic testing in the rapid diagnosis of Danon disease, underscoring the need to routinely consider the inclusion of LAMP2 gene in the genetic screening for HCM, since an early diagnosis of Danon disease in patients with a phenotype mimicking HCM is essential to plan appropriate treatment, ie cardiac transplantation.
| S-EPMC7132987 | biostudies-literature
Project description:IntroductionThe yield of genetic testing in hypertrophic cardiomyopathy (HCM) is variable. The Mayo HCM Genotype Predictor score (Mayo Score) provides the pre-test probability of a positive HCM genetic test. In the original cohort of Mayo Score patients, only 9 HCM-associated myofilament genes were evaluated. The aim of this study was to validate the Mayo Score in the national HCM cohort and assess the yield of genetic testing using next generation sequencing (NGS) evaluating up to 229 genes.Material and methodsWe included 336 consecutive unrelated HCM patients (41% women, mean age: 53 ±15 years). We performed NGS-based genomic testing with classification of identified variants according to American College of Medical Genetics and Genomics guidelines. NGS findings were compared with the Mayo Score (ranging from -1 to 5) based on clinical and echocardiographic variables.ResultsWe identified 72 variants classified as pathogenic or likely pathogenic in 70 (21%) HCM patients. One patient with the highest Mayo Score of 5 had a pathogenic mutation (100% yield). Patients with a Mayo Score of 4 had a pathogenic mutation in 71% of cases. Patients with a Mayo Score of 3 or 2 had a pathogenic mutation in 50 and 35% of cases, respectively. The yield of genetic testing in patients with a Mayo Score of -1 to 1 was low (6-21%).ConclusionsThe overall yield of genetic testing using NGS evaluating up to 229 genes was low. The yield of genetic testing was consistently predicted with Mayo Score values.
| S-EPMC6524174 | biostudies-literature
Project description:Next-generation sequencing (NGS) of tumor tissue (ie, clinical sequencing) can guide clinical management by providing information about actionable gene aberrations that have diagnostic and therapeutic significance. Here, we undertook a hospital-based prospective study (TOP-GEAR project, 2nd stage) to investigate the feasibility and utility of NGS-based analysis of 114 cancer-associated genes (the NCC Oncopanel test). We examined 230 cases (comprising more than 30 tumor types) of advanced solid tumors, all of which were matched with nontumor samples. Gene profiling data were obtained for 187 cases (81.3%), 111 (59.4%) of which harbored actionable gene aberrations according to the Clinical Practice Guidelines for Next Generation Sequencing in Cancer Diagnosis and Treatment (Edition 1.0) issued by 3 major Japanese cancer-related societies. Twenty-five (13.3%) cases have since received molecular-targeted therapy according to their gene aberrations. These results indicate the utility of tumor-profiling multiplex gene panel testing in a clinical setting in Japan. This study is registered with UMIN Clinical Trials Registry (UMIN 000011141).
| S-EPMC6447843 | biostudies-literature
Project description:Next-generation sequencing has led to transformative advances in our ability to diagnose rare diseases by simultaneously sequencing dozens, hundreds, or even entire genomes worth of genes to efficiently identify pathogenic mutations. These studies amount to multiple hypothesis testing on a massive scale and not infrequently lead to discovery of multiple genetic variants whose relative contributions to a patient's disease are unclear. Panel testing, in particular, can be problematic because each of the many genes being sequenced might represent a plausible explanation for a given case. We performed targeted gene panel analysis of 43 established neuromuscular disease genes in a patient with congenital fiber-type disproportion (CFTD) and fatal infantile cardiomyopathy. Initial review of variants identified changes in four genes that could be considered relevant candidates to cause this child's disease. Further analysis revealed that two of these are likely benign, but a homozygous frameshift variant in the myosin light chain 2 gene, MYL2, and a heterozygous nonsense mutation in the nebulin gene, NEB, met criteria to be classified as likely pathogenic or pathogenic. Recessive MYL2 mutations are a rare cause of CFTD associated with both skeletal and cardiomyopathy, whereas recessive NEB mutations cause nemaline myopathy. Although the proband's phenotype is likely largely explained by the MYL2 variant, the heterozygous pathogenic NEB variant cannot be ruled out as a contributing factor. This case illustrates the complexity when analyzing large numbers of variants from targeted gene panels in which each of the genes might plausibly contribute to the patient's clinical presentation.
| S-EPMC6672024 | biostudies-literature
Project description:The diagnosis of myeloid neoplasms (MN) has significantly evolved through the last few decades. Next Generation Sequencing (NGS) is gradually becoming an essential tool to help clinicians with disease management. To this end, most specialized genetic laboratories have implemented NGS panels targeting a number of different genes relevant to MN. The aim of the present study is to evaluate the performance of four different targeted NGS gene panels based on their technical features and clinical utility. A total of 32 patient bone marrow samples were accrued and sequenced with 3 commercially available panels and 1 custom panel. Variants were classified by two geneticists based on their clinical relevance in MN. There was a difference in panel's depth of coverage. We found 11 discordant clinically relevant variants between panels, with a trend to miss long insertions. Our data show that there is a high risk of finding different mutations depending on the panel of choice, due both to the panel design and the data analysis method. Of note, CEBPA, CALR and FLT3 genes, remains challenging the use of NGS for diagnosis of MN in compliance with current guidelines. Therefore, conventional molecular testing might need to be kept in place for the correct diagnosis of MN for now.
| S-EPMC6980571 | biostudies-literature