Diagnostic Yield of Genetic Testing in Young Patients With Atrioventricular Block of Unknown Cause.
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SUBMITTER: Resdal Dyssekilde J
PROVIDER: S-EPMC9238593 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimsAtrioventricular block (AVB) of unknown aetiology is rare in the young, and outcome in these patients is unknown. We aimed to assess long-term morbidity and mortality in young patients with AVB of unknown aetiology.Methods and resultsWe identified all Danish patients younger than 50 years receiving a first pacemaker due to AVB between January 1996 and December 2015. By reviewing medical records, we included patients with AVB of unknown aetiology. A matched control cohort was established. Follow-up was performed using national registries. The primary outcome was a composite endpoint consisting of death, heart failure hospitalization, ventricular tachyarrhythmia, and cardiac arrest with successful resuscitation. We included 517 patients, and 5170 controls. Median age at first pacemaker implantation was 41.3 years [interquartile range (IQR) 32.7-46.2 years]. After a median follow-up of 9.8 years (IQR 5.7-14.5 years), the primary endpoint had occurred in 14.9% of patients and 3.2% of controls [hazard ratio (HR) 3.8; 95% confidence interval (CI) 2.9-5.1; P < 0.001]. Patients with persistent AVB at time of diagnosis had a higher risk of the primary endpoint (HR 10.6; 95% CI 5.7-20.0; P < 0.001), and risk was highest early in the follow-up period (HR 6.8; 95% CI 4.6-10.0; P < 0.001, during 0-5 years of follow-up).ConclusionAtrioventricular block of unknown aetiology presenting before the age of 50 years and treated with pacemaker implantation was associated with a three- to four-fold higher rate of the composite endpoint of death or hospitalization for heart failure, ventricular tachyarrhythmia, or cardiac arrest with successful resuscitation. Patients with persistent AVB were at higher risk. These findings warrant improved follow-up strategies for young patients with AVB of unknown aetiology.
| S-EPMC8169155 | biostudies-literature
Project description:AimsTo investigate the role of genetic testing in patients with idiopathic atrioventricular conduction disease requiring pacemaker (PM) implantation before the age of 50 years.Methods and resultsAll consecutive PM implantations in Southern Switzerland between 2010 and 2019 were evaluated. Inclusion criteria were: (i) age at the time of PM implantation: < 50 years; (ii) atrioventricular block (AVB) of unknown aetiology. Study population was investigated by ajmaline challenge and echocardiographic assessment over time. Genetic testing was performed using next-generation sequencing panel, containing 174 genes associated to inherited cardiac diseases, and Sanger sequencing confirmation of suspected variants with clinical implication. Of 2510 patients who underwent PM implantation, 15 (0.6%) were young adults (median age: 44 years, male predominance) presenting with advanced AVB of unknown origin. The average incidence of idiopathic AVB computed over the 2010-2019 time window was 0.7 per 100 000 persons per year (95% CI 0.4-1.2). Most of patients (67%) presented with specific genetic findings (pathogenic variant) or variants of uncertain significance (VUS). A pathogenic variant of PKP2 gene was found in one patient (6.7%) with no overt structural cardiac abnormalities. A VUS of TRPM4, MYBPC3, SCN5A, KCNE1, LMNA, GJA5 genes was found in other nine cases (60%). Of these, three unrelated patients (20%) presented the same heterozygous missense variant c.2531G > A p.(Gly844Asp) in TRPM4 gene. Diagnostic re-assessment over time led to a diagnosis of Brugada syndrome and long-QT syndrome in two patients (13%). No cardiac events occurred during a median follow-up of 72 months.ConclusionIdiopathic AVB in adults younger than 50 years is a very rare condition with an incidence of 0.7 per 100 000 persons/year. Systematic investigations, including genetic testing and ajmaline challenge, can lead to the achievement of a specific diagnosis in up to 20% of patients. Heterozygous missense variant c.2531G > A p.(Gly844Asp) in TRPM4 gene was found in an additional 20% of unrelated patients, suggesting possible association of the variant with the disease.
| S-EPMC9934995 | biostudies-literature
Project description:IntroductionAnalysis of fibrinolytic disorders is challenging and may potentially lead to underdiagnosis of patients with an increased bleeding tendency.AimTo compare clinical characteristics, laboratory measurements, and treatment modalities in a monocenter cohort of patients in whom fibrinolytic studies were performed.MethodsRetrospective study of patients in whom fibrinolytic studies were performed between January 2016 and February 2020 in the Hemophilia Treatment Center, Nijmegen-Eindhoven-Maastricht, the Netherlands. Plasminogen activator inhibitor type 1 (PAI-1) antigen and activity level, α2-antiplasmin activity, tissue plasminogen activator, and euglobulin clot lysis time (ECLT) before and after venous compression were determined in all patients. Data of bleeding assessment tool (BAT) score, clinical characteristics, results of primary and secondary hemostasis assays, and general treatment plans were collected.ResultsIn total, 160 patients were included: 97 (61%) without and 63 (39%) with a laboratory-based fibrinolytic disorder. Mean BAT score did not differ between the groups (9.3 vs 9.8, respectively). The presumptive fibrinolytic disorders were distributed as follows: 34 patients had an increased ECLT ratio or low baseline ECLT, 25 patients had low PAI-1 antigen and activity level, and four patients had both. The majority of these patients were treated with tranexamic acid monotherapy (60%) with only 40% additional treatment options, whereas 80% of patients without a presumptive fibrinolytic disorder had multiple treatment modalities.DiscussionAnalysis of fibrinolytic disorders in selected patients has a high diagnostic yield. General incorporation of fibrinolytic analysis in the diagnostic workup of patients with bleeding of unknown cause can improve diagnosis and management of their bleeding episodes.
| S-EPMC8922970 | biostudies-literature
Project description:BackgroundGenetic testing (GT) for hereditary cancer predisposition is traditionally performed on selected genes based on established guidelines for each cancer type. Recently, expanded GT (eGT) using large hereditary cancer gene panels uncovered hereditary predisposition in a greater proportion of patients than previously anticipated. We sought to define the diagnostic yield of eGT and its clinical relevance in a broad cancer patient population over a 5-year period.MethodsA total of 17,523 cancer patients with a broad range of solid tumors, who received eGT at Memorial Sloan Kettering Cancer Center between July 2015 to April 2020, were included in the study. The patients were unselected for current GT criteria such as cancer type, age of onset, and/or family history of disease. The diagnostic yield of eGT was determined for each cancer type. For 9187 patients with five common cancer types frequently interrogated for hereditary predisposition (breast, colorectal, ovarian, pancreatic, and prostate cancer), the rate of pathogenic/likely pathogenic (P/LP) variants in genes that have been associated with each cancer type was analyzed. The clinical implications of additional findings in genes not known to be associated with a patients' cancer type were investigated.Results16.7% of patients in a broad cancer cohort had P/LP variants in hereditary cancer predisposition genes identified by eGT. The diagnostic yield of eGT in patients with breast, colorectal, ovarian, pancreatic, and prostate cancer was 17.5%, 15.3%, 24.2%, 19.4%, and 15.9%, respectively. Additionally, 8% of the patients with five common cancers had P/LP variants in genes not known to be associated with the patient's current cancer type, with 0.8% of them having such a variant that confers a high risk for another cancer type. Analysis of clinical and family histories revealed that 74% of patients with variants in genes not associated with their current cancer type but which conferred a high risk for another cancer did not meet the current GT criteria for the genes harboring these variants. One or more variants of uncertain significance were identified in 57% of the patients.ConclusionsCompared to targeted testing approaches, eGT can increase the yield of detection of hereditary cancer predisposition in patients with a range of tumors, allowing opportunities for enhanced surveillance and intervention. The benefits of performing eGT should be weighed against the added number of VUSs identified with this approach.
| S-EPMC9377129 | biostudies-literature
Project description:BackgroundGenetic testing in hypertrophic cardiomyopathy (HCM) is a published guideline-based recommendation. The diagnostic yield of genetic testing and corresponding HCM-associated genes have been largely documented by single center studies and carefully selected patient cohorts. Our goal was to evaluate the diagnostic yield of genetic testing in a heterogeneous cohort of patients with a clinical suspicion of HCM, referred for genetic testing from multiple centers around the world.MethodsA retrospective review of patients with a suspected clinical diagnosis of HCM referred for genetic testing at Blueprint Genetics was undertaken. The analysis included syndromic, myopathic and metabolic etiologies. Genetic test results and variant classifications were extracted from the database. Variants classified as pathogenic (P) or likely pathogenic (LP) were considered diagnostic.ResultsA total of 1376 samples were analyzed. Three hundred and sixty-nine tests were diagnostic (26.8%); 373 P or LP variants were identified. Only one copy number variant was identified. The majority of diagnostic variants involved genes encoding the sarcomere (85.0%) followed by 4.3% of diagnostic variants identified in the RASopathy genes. Two percent of diagnostic variants were in genes associated with a cardiomyopathy other than HCM or an inherited arrhythmia. Clinical variables that increased the likelihood of identifying a diagnostic variant included: an earlier age at diagnosis (p < 0.0001), a higher maximum wall thickness (MWT) (p < 0.0001), a positive family history (p < 0.0001), the absence of hypertension (p = 0.0002), and the presence of an implantable cardioverter-defibrillator (ICD) (p = 0.0004).ConclusionThe diagnostic yield of genetic testing in this heterogeneous cohort of patients with a clinical suspicion of HCM is lower than what has been reported in well-characterized patient cohorts. We report the highest yield of diagnostic variants in the RASopathy genes identified in a laboratory cohort of HCM patients to date. The spectrum of genes implicated in this unselected cohort highlights the importance of pre-and post-test counseling when offering genetic testing to the broad HCM population.
| S-EPMC7934228 | biostudies-literature
Project description:This retrospective cohort study was designed to determine the yield of genetic tests in hypotonic infants and develop a diagnostic algorithm. Out of 496 patients identified by International Classification of Diseases (ICD) 9/10 coding, 324 patients met the inclusion criteria. Diagnostic yields were 32% for karyotype, 19% for microarray, 30% for targeted genetic tests, 38% for gene panels, and 31% for exome sequencing. In addition, we considered the diagnostic contribution of ancillary tests, including neuroimaging, metabolic tests, and so forth. The combination of microarray and exome sequencing gave the highest diagnostic yield. None of the other tests added significant value in arriving at a diagnosis. Based on these results we propose that the vast majority of infants with congenital hypotonia should start with a microarray and proceed with exome sequencing, with the notable exception of infants with clearly syndromic features in whom karyotyping or targeted testing may be more appropriate.
| S-EPMC9291145 | biostudies-literature
Project description:Recent several studies have shown that the genetic variation of SCN5A is related with atrioventricular conduction block (AVB); no study has yet been published in Koreans. Therefore, to determine the AVB-associated genetic variation in Korean patients, we investigated the genetic variation of SCN5A in Korean patients with AVB and compared with normal control subjects. We enrolled 113 patients with AVB and 80 normal controls with no cardiac symptoms. DNA was isolated from the peripheral blood, and all exons (exon 2-exon 28) except the untranslated region and exon-intron boundaries of the SCN5A gene were amplified by multiplex PCR and directly sequenced using an ABI PRISM 3100 Genetic Analyzer. When a variation was discovered in genomic DNA from AVB patients, we confirmed whether the same variation existed in the control genomic DNA. In the present study, a total of 7 genetic variations were detected in 113 AVB patients. Of the 7 variations, 5 (G87A-A29A, intervening sequence 9-3C>A, A1673G-H558R, G3578A-R1193Q, and T5457C-D1819D) have been reported in previous studies, and 2 (C48G-F16L and G3048A-T1016T) were novel variations that have not been reported. The 2 newly discovered variations were not found in the 80 normal controls. In addition, G298S, G514C, P1008S, G1406R, and D1595N, identified in other ethnic populations, were not detected in this study. We found 2 novel genetic variations in the SCN5A gene in Korean patients with AVB. However, further functional study might be needed.
| S-EPMC3480677 | biostudies-literature
Project description:AimsTo describe aetiologies and temporal trends in young patients with atrioventricular block (AVB).Methods and resultsWe identified all patients in Denmark, receiving their first pacemaker because of AVB before the age of 50?years between 1996 and 2015. Medical records were reviewed and clinical information and diagnostic work-up results were obtained to evaluate the aetiology. We used Poisson regression testing for temporal trends. One thousand and twenty-seven patients were identified, median age at time of implantation was 38 (interquartile range 25-45) years, 584 (56.9%) were male. The aetiologies were complications to cardiac surgery [n?=?157 (15.3%)], congenital AVB [n?=?93 (9.0%)], cardioinhibitory reflex [n?=?52 (5.0%)], congenital heart disease [n?=?43 (4.2%)], complication to radiofrequency ablation [n?=?35 (3.4%)], cardiomyopathy [n?=?31 (3.0%)], endocarditis [n?=?18 (1.7%)], muscular dystrophy [n?=?14 (1.4%)], ischaemic heart disease [n?=?14 (1.4%)], sarcoidosis [n?=?11 (1.1%)], borreliosis [n?=?9 (0.9%)], hereditary [n?=?6 (0.6%)], side-effect to antiarrhythmics [n?=?6 (0.6%)], planned His-ablation [n?=?5 (0.5%)], complication to alcohol septal ablation [n?=?5 (0.5%)], and other known aetiologies [n?=?11 (1.1%)]. The aetiology remained unknown in 517 (50.3%) cases. While the number of patients with unknown aetiology increased during the study period (P?<?0.001), we observed no significant change in the number of patients with identified aetiology (P?=?0.35).ConclusionIn a nationwide cohort, the aetiology of AVB was identified in only half the patients younger than 50?years referred for first-time pacemaker implantation. The number of patients with unknown aetiology increased during the study period. These findings indicate need for better insight into aetiologies of AVB and improved diagnostic work-up guidelines.
| S-EPMC6826204 | biostudies-literature
Project description:Thirty percent of all inherited retinal disease (IRD) is accounted for by conditions with extra-ocular features. This study aimed to establish the genetic diagnostic pick-up rate for IRD patients with one or more extra-ocular features undergoing panel-based screening in a clinical setting. One hundred and six participants, tested on a gene panel which contained both isolated and syndromic IRD genes, were retrospectively ascertained from the Manchester Genomic Diagnostics Laboratory database spanning 6 years (2012-2017). Phenotypic features were extracted from the clinical notes and classified according to Human Phenotype Ontology; all identified genetic variants were interpreted in accordance to the American College of Medical Genetics and Genomics guidelines. Overall, 49% (n?=?52) of patients received a probable genetic diagnosis. A further 6% (n?=?6) had a single disease-associated variant in an autosomal recessive disease-relevant gene. Fifty-two percent (n?=?55) of patients had a clinical diagnosis at the time of testing. Of these, 71% (n?=?39) received a probable genetic diagnosis. By contrast, for those without a provisional clinical diagnosis (n?=?51), only 25% (n?=?13) received a probable genetic diagnosis. The clinical diagnosis of Usher (n?=?33) and Bardet-Biedl syndrome (n?=?10) was confirmed in 67% (n?=?22) and 80% (n?=?8), respectively. The testing diagnostic rate in patients with clinically diagnosed multisystemic IRD conditions was significantly higher than those without one (71% versus 25%; p value?<?0.001). The lower pick-up rate in patients without a clinical diagnosis suggests that panel-based approaches are unlikely to be the most effective means of achieving a molecular diagnosis for this group. Here, we suggest that genome-wide approaches (whole exome or genome) are more appropriate.
| S-EPMC7171123 | biostudies-literature
Project description:Reflex atrioventricular block is well-recorded although it is considered rare. Recent data suggests that it is less rare than has been supposed. It has been shown to occur in both vasovagal and carotid sinus reflexes. It has to be distinguished from paroxysmal atrioventricular block due to ventricular conduction tissue disease. Low chronic adenosine levels combined with adenosine release may mimic reflex atrioventricular block. Explanations of the mechanism of these phenomena have been lacking until the recent past. The relevance of reflex atrioventricular block to clinical decision-making is as a possible indication for pacing the heart with consideration given to the vasodepressor component of the reflex.
| S-EPMC7145901 | biostudies-literature