Circulation: Cardiovascular Genetics最新文献

{"title":"Predicting the Functional Impact of KCNQ1 Variants of Unknown Significance.","authors":"Bian Li,&nbsp;Jeffrey L Mendenhall,&nbsp;Brett M Kroncke,&nbsp;Keenan C Taylor,&nbsp;Hui Huang,&nbsp;Derek K Smith,&nbsp;Carlos G Vanoye,&nbsp;Jeffrey D Blume,&nbsp;Alfred L George,&nbsp;Charles R Sanders,&nbsp;Jens Meiler","doi":"10.1161/CIRCGENETICS.117.001754","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001754","url":null,"abstract":"<p><strong>Background: </strong>An emerging standard-of-care for long-QT syndrome uses clinical genetic testing to identify genetic variants of the KCNQ1 potassium channel. However, interpreting results from genetic testing is confounded by the presence of variants of unknown significance for which there is inadequate evidence of pathogenicity.</p><p><strong>Methods and results: </strong>In this study, we curated from the literature a high-quality set of 107 functionally characterized KCNQ1 variants. Based on this data set, we completed a detailed quantitative analysis on the sequence conservation patterns of subdomains of KCNQ1 and the distribution of pathogenic variants therein. We found that conserved subdomains generally are critical for channel function and are enriched with dysfunctional variants. Using this experimentally validated data set, we trained a neural network, designated Q1VarPred, specifically for predicting the functional impact of KCNQ1 variants of unknown significance. The estimated predictive performance of Q1VarPred in terms of Matthew's correlation coefficient and area under the receiver operating characteristic curve were 0.581 and 0.884, respectively, superior to the performance of 8 previous methods tested in parallel. Q1VarPred is publicly available as a web server at http://meilerlab.org/q1varpred.</p><p><strong>Conclusions: </strong>Although a plethora of tools are available for making pathogenicity predictions over a genome-wide scale, previous tools fail to perform in a robust manner when applied to KCNQ1. The contrasting and favorable results for Q1VarPred suggest a promising approach, where a machine-learning algorithm is tailored to a specific protein target and trained with a functionally validated data set to calibrate informatics tools.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001754","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35597824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Commercially Available Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Another Piece in Our Tool Box, but Not a Swiss Army Knife Yet.","authors":"Leif-Hendrik Boldt,&nbsp;Abdul S Parwani,&nbsp;Frank R Heinzel","doi":"10.1161/CIRCGENETICS.117.001913","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001913","url":null,"abstract":"KCNJ2 encodes the pore-forming α-subunit of the Kir2.1 inward-rectifier potassium channel, the main determinant of the current (I K1 ), which is responsible for the final repolarization phase of the ventricular action potential, as well as a stable resting membrane potential in the working myocardium. Variants in the KCNJ2 gene have been associated with familial atrial fibrillation (gain of function), short-QT syndrome (gain of function), catecholaminergic polymorphic ventricular tachycardia; loss of function), as well as the Andersen–Tawil syndrome (ATS; loss of function). ATS is a rare hereditary multisystem disorder leading to periodic paralysis, dysmorphic features, and ventricular arrhythmias. Penetrance of the disease is extremely variable, and not all patients present with the full triad of symptoms. Regarding the cardiac phenotype, these patients present with frequent polymorphic ventricular contractions and bidirectional ventricular tachycardia. Typically, these arrhythmias are present at rest and disappear during exercise. This is an important differentiation from catecholaminergic polymorphic ventricular tachycardia, which also presents with bidirectional tachycardia, but typically during catecholaminergic stimulation or exercise. ATS patients frequently show prominent U waves in the ECG, and some also show prolongation of the corrected QT interval. Although QT prolongation is not a typical sign, ATS was classified as LQTS-subtype (LQT7).","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001913","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35597826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Care in Specialized Centers and Data Sharing Increase Agreement in Hypertrophic Cardiomyopathy Genetic Test Interpretation.","authors":"Aisha Furqan,&nbsp;Patricia Arscott,&nbsp;Francesca Girolami,&nbsp;Allison L Cirino,&nbsp;Michelle Michels,&nbsp;Sharlene M Day,&nbsp;Iacopo Olivotto,&nbsp;Carolyn Y Ho,&nbsp;Euan Ashley,&nbsp;Eric M Green,&nbsp;Colleen Caleshu","doi":"10.1161/CIRCGENETICS.116.001700","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001700","url":null,"abstract":"<p><strong>Background: </strong>Clinically impactful differences in the interpretation of genetic test results occur between laboratories and clinicians. To improve the classification of variants, a better understanding of why discrepancies occur and how they can be reduced is needed.</p><p><strong>Methods and results: </strong>We examined the frequency, causes, and resolution of discordant variant classifications in the Sarcomeric Human Cardiomyopathy Registry (SHaRe), a consortium of international centers with expertise in the clinical management and genetic architecture of hypertrophic cardiomyopathy. Of the 112 variants present in patients at >1 center, 23 had discordant classifications among centers (20.5%; Fleiss κ, 0.54). Discordance was more than twice as frequent among clinical laboratories in ClinVar, a public archive of variant classifications (315/695 variants; 45.2%; Fleiss κ, 0.30; <i>P</i><0.001). Discordance in SHaRe most frequently occurred because hypertrophic cardiomyopathy centers had access to different privately held data when making their classifications (75.0%). Centers reassessed their classifications based on a comprehensive and current data summary, leading to reclassifications that reduced the discordance rate from 20.5% to 10.7%. Different interpretations of rarity and co-occurrence with pathogenic variants contributed to residual discordance.</p><p><strong>Conclusions: </strong>Discordance in variant classification among hypertrophic cardiomyopathy centers is largely attributable to privately held data. Some discrepancies are caused by differences in expert assessment of conflicting data. Discordance was markedly lower among centers specialized in hypertrophic cardiomyopathy than among clinical laboratories, suggesting that optimal genetic test interpretation occurs in the context of clinical care delivered by specialized centers with both clinical and genetics expertise.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001700","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35479274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction for Intravenous Immunoglobulin Resistance by Using Weighted Genetic Risk Score Identified From Genome-Wide Association Study in Kawasaki Disease.","authors":"Ho-Chang Kuo,&nbsp;Henry Sung-Ching Wong,&nbsp;Wei-Pin Chang,&nbsp;Ben-Kuen Chen,&nbsp;Mei-Shin Wu,&nbsp;Kuender D Yang,&nbsp;Kai-Sheng Hsieh,&nbsp;Yu-Wen Hsu,&nbsp;Shih-Feng Liu,&nbsp;Xiao Liu,&nbsp;Wei-Chiao Chang","doi":"10.1161/CIRCGENETICS.116.001625","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001625","url":null,"abstract":"<p><strong>Background: </strong>Intravenous immunoglobulin (IVIG) is the treatment of choice in Kawasaki disease (KD). IVIG is used to prevent cardiovascular complications related to KD. However, a proportion of KD patients have persistent fever after IVIG treatment and are defined as IVIG resistant.</p><p><strong>Methods and results: </strong>To develop a risk scoring system based on genetic markers to predict IVIG responsiveness in KD patients, a total of 150 KD patients (126 IVIG responders and 24 IVIG nonresponders) were recruited for this study. A genome-wide association analysis was performed to compare the 2 groups and identified risk alleles for IVIG resistance. A weighted genetic risk score was calculated by the natural log of the odds ratio multiplied by the number of risk alleles. Eleven single-nucleotide polymorphisms were identified by genome-wide association study. The KD patients were categorized into 3 groups based on their calculated weighted genetic risk score. Results indicated a significant association between weighted genetic risk score (groups 3 and 4 versus group 1) and the response to IVIG (Fisher's exact <i>P</i> value 4.518×10^-⁰³ and 8.224×10^-¹⁰, respectively).</p><p><strong>Conclusions: </strong>This is the first weighted genetic risk score study based on a genome-wide association study in KD. The predictive model integrated the additive effects of all 11 single-nucleotide polymorphisms to provide a prediction of the responsiveness to IVIG.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001625","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35508495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation.","authors":"Hannah G van Velzen,&nbsp;Arend F L Schinkel,&nbsp;Rogier A Oldenburg,&nbsp;Marjon A van Slegtenhorst,&nbsp;Ingrid M E Frohn-Mulder,&nbsp;Jolanda van der Velden,&nbsp;Michelle Michels","doi":"10.1161/CIRCGENETICS.116.001660","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001660","url":null,"abstract":"<p><strong>Background: </strong><i>MYBPC3</i> (Myosin-binding protein C) founder mutations account for 35% of hypertrophic cardiomyopathy (HCM) cases in the Netherlands. We compared clinical characteristics and outcome of <i>MYBPC3</i> founder mutation (FG+) HCM with nonfounder genotype-positive (G+) and genotype-negative (G-) HCM.</p><p><strong>Methods and results: </strong>The study included 680 subjects: 271 FG+ carriers, 132 G+ probands with HCM, and 277 G- probands with HCM. FG+ carriers included 134 FG+ probands with HCM, 54 FG+ relatives diagnosed with HCM after family screening, 74 FG+/phenotype-negative relatives, and 9 with noncompaction or dilated cardiomyopathy. The clinical phenotype of FG+ and G+ probands with HCM was similar. FG+ and G+ probands were younger with less left ventricular outflow tract obstruction than G- probands, however, had more hypertrophy, and nonsustained ventricular tachycardia. FG+ relatives with HCM had less hypertrophy, smaller left atria, and less systolic and diastolic dysfunction than FG+ probands with HCM. After 8±6 years, cardiovascular mortality in FG+ probands with HCM was similar to G+ HCM (22% versus 14%; log-rank <i>P</i>=0.14), but higher than G- HCM (22% versus 6%; log-rank <i>P</i><0.001) and FG+ relatives with HCM (22% versus 4%; <i>P</i>=0.009). Cardiac events were absent in FG+/phenotype-negative relatives; subtle HCM developed in 11% during 6 years of follow-up.</p><p><strong>Conclusions: </strong>Clinical phenotype and outcome of FG+ HCM was similar to G+ HCM but worse than G- HCM and FG+ HCM diagnosed in the context of family screening. These findings indicate the need for more intensive follow-up of FG+ and G+ HCM versus G- HCM and FG+ HCM in relatives.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001660","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35399913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Navigating Genetic and Phenotypic Uncertainty in Left Ventricular Noncompaction.","authors":"June-Wha Rhee,&nbsp;Megan E Grove,&nbsp;Euan A Ashley","doi":"10.1161/CIRCGENETICS.117.001857","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001857","url":null,"abstract":"Once called spongiform cardiomyopathy for its distinct lace-like morphology, left ventricular noncompaction (LVNC) describes a ventricular wall with a prominent noncompacted layer; the excessive trabeculations and deep intertrabecular recesses are separated by thin compacted myocardium.1,2 The diagnosis of LVNC is made primarily by imaging studies to index the thickness of the trabeculated layer to that of the compacted layer. With the advent of cardiac magnetic resonance allowing for high-resolution imaging of the myocardium, hypertrabeculation in the LV has become increasingly recognized in clinical practice. Significant individual variability exists in the extent of trabeculation, however, making its diagnosis extremely challenging. In addition, LVNC frequently occurs in association with other cardiomyopathies,2 congenital heart defects,3 neuromuscular disorders, and genetic syndromes. As a result, there has been ongoing debate as to whether LVNC is an independent disease entity, a clinical phenotype shared among various cardiomyopathies, or a mere bystander.2 Contributing to this debate is the little data on the genetic architecture underlying LVNC. Although the next-generation sequencing has facilitated comprehensive and cost-effective approaches to identify potentially causative genetic variation in LVNC, the ability to identify such variation has outpaced our capacity to clearly interpret its clinical significance. Thus, in this era of rapidly evolving clinical imaging and sequencing technologies, there is a pressing need to integrate the accumulating imaging and genetic data in a large cohort, to better understand the entity that is LVNC.\u0000\u0000See Article by Author\u0000\u0000In this issue of Circulation: Cardiovascular Genetics , Jefferies et al4 expand on the known genetic causes of LVNC and provide insights into the genetic landscape of LVNC and LV hypertrabeculation (LVHT) in the largest prospective cohort to date. By leveraging whole exome sequencing and cardiac magnetic resonance, the research team has assembled a deeply genotyped and phenotyped study …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001857","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35401814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fabry Disease: A Rare Condition Emerging From the Darkness.","authors":"Perry M Elliott","doi":"10.1161/CIRCGENETICS.117.001862","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001862","url":null,"abstract":"Fabry (or Anderson–Fabry) disease—first described in 1898 by Johannes Fabry in Germany and William Anderson in England—is a lysosomal storage disease caused by mutations in the GLA gene located on the X chromosome (Xq22.1).1 These cause deficiency of the enzyme aGal A (alpha galactosidase A) and the accumulation of glycosphingolipids, particularly globotriaosylceramide, in different cell types. Over 800 individual missense or nonsense point mutations, splicing mutations, deletions, and insertions are reported, the majority of which render the aGal A enzyme nonfunctional.2 Some variants are associated with residual aGal A activity (typically 2%–20% of normal values) that results in attenuated forms of the disease. Although Fabry disease (FD) is an X–linked trait, women with GLA mutations can develop signs and symptoms of FD, which are usually milder than seen in affected men but cases of severe disease are well recognized, possibly as the result of skewed X chromosome inactivation.3\u0000\u0000See Article by Adalsteinsdottir et al \u0000\u0000In this edition of the journal, Adalsteinsdottir et al4 describe the clinical phenotypes of 2 families—identified during genetic screening …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001862","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35401816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes.","authors":"Berglind Adalsteinsdottir,&nbsp;Runolfur Palsson,&nbsp;Robert J Desnick,&nbsp;Marianna Gardarsdottir,&nbsp;Polakit Teekakirikul,&nbsp;Martin Maron,&nbsp;Evan Appelbaum,&nbsp;Ulf Neisius,&nbsp;Barry J Maron,&nbsp;Michael A Burke,&nbsp;Brenden Chen,&nbsp;Silvere Pagant,&nbsp;Christoffer V Madsen,&nbsp;Ragnar Danielsen,&nbsp;Reynir Arngrimsson,&nbsp;Ulla Feldt-Rasmussen,&nbsp;Jonathan G Seidman,&nbsp;Christine E Seidman,&nbsp;Gunnar Th Gunnarsson","doi":"10.1161/CIRCGENETICS.116.001639","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001639","url":null,"abstract":"<p><strong>Background: </strong>The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by <i>GLA</i>(α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B).</p><p><strong>Methods and results: </strong>Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes). Clinical assessments, α-galactosidase A (α-GalA) activities, glycosphingolipid substrate levels, and in vitro mutation expression were used to categorize p.D322E as a classic FD mutation and p.I232T as a later-onset FD mutation. In vitro expression revealed that p.D322E and p.I232T had α-GalA activities of 1.4% and 14.9% of the mean wild-type activity, respectively. Family A men had markedly decreased α-GalA activity and childhood-onset classic manifestations, except for angiokeratoma and cornea verticillata. Family B men had residual α-GalA activity and developed FD manifestations in adulthood. Despite these differences, all family A and family B men >30 years of age had left ventricular hypertrophy, which was mainly asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations.</p><p><strong>Conclusions: </strong>Men with classic or later-onset FD caused by <i>GLA</i> missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different α-GalA activities.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001639","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35314359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Lamin A/C</i>-Related Cardiac Disease: Late Onset With a Variable and Mild Phenotype in a Large Cohort of Patients With the Lamin A/C p.(Arg331Gln) Founder Mutation.","authors":"Edgar T Hoorntje,&nbsp;Ilse A Bollen,&nbsp;Daniela Q Barge-Schaapveld,&nbsp;Florence H van Tienen,&nbsp;Gerard J Te Meerman,&nbsp;Joeri A Jansweijer,&nbsp;Anthonie J van Essen,&nbsp;Paul G Volders,&nbsp;Alina A Constantinescu,&nbsp;Peter C van den Akker,&nbsp;Karin Y van Spaendonck-Zwarts,&nbsp;Rogier A Oldenburg,&nbsp;Carlo L Marcelis,&nbsp;Jasper J van der Smagt,&nbsp;Eric A Hennekam,&nbsp;Aryan Vink,&nbsp;Marianne Bootsma,&nbsp;Emmelien Aten,&nbsp;Arthur A Wilde,&nbsp;Arthur van den Wijngaard,&nbsp;Jos L Broers,&nbsp;Jan D Jongbloed,&nbsp;Jolanda van der Velden,&nbsp;Maarten P van den Berg,&nbsp;J Peter van Tintelen","doi":"10.1161/CIRCGENETICS.116.001631","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.116.001631","url":null,"abstract":"<p><strong>Background: </strong>Interpretation of missense variants can be especially difficult when the variant is also found in control populations. This is what we encountered for the <i>LMNA</i> c.992G>A (p.(Arg331Gln)) variant. Therefore, to evaluate the effect of this variant, we combined an evaluation of clinical data with functional experiments and morphological studies.</p><p><strong>Methods and results: </strong>Clinical data of 23 probands and 35 family members carrying this variant were retrospectively collected. A time-to-event analysis was performed to compare the course of the disease with carriers of other <i>LMNA</i> mutations. Myocardial biopsies were studied with electron microscopy and by measuring force development of the sarcomeres. Morphology of the nuclear envelope was assessed with immunofluorescence on cultured fibroblasts. The phenotype in probands and family members was characterized by atrioventricular conduction disturbances (61% and 44%, respectively), supraventricular arrhythmias (69% and 52%, respectively), and dilated cardiomyopathy (74% and 14%, respectively). LMNA p.(Arg331Gln) carriers had a significantly better outcome regarding the composite end point (malignant ventricular arrhythmias, end-stage heart failure, or death) compared with carriers of other pathogenic <i>LMNA</i> mutations. A shared haplotype of 1 Mb around <i>LMNA</i> suggested a common founder. The combined logarithm of the odds score was 3.46. Force development in membrane-permeabilized cardiomyocytes was reduced because of decreased myofibril density. Structural nuclear <i>LMNA</i>-associated envelope abnormalities, that is, blebs, were confirmed by electron microscopy and immunofluorescence microscopy.</p><p><strong>Conclusions: </strong>Clinical, morphological, functional, haplotype, and segregation data all indicate that LMNA p.(Arg331Gln) is a pathogenic founder mutation with a phenotype reminiscent of other <i>LMNA</i> mutations but with a more benign course.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001631","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35393651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards Point-of-Care Measurements Using Noncoding RNAs: A Novel Tool to Monitor Aggravation of Advanced Atherosclerotic Lesions.","authors":"Valentina Paloschi,&nbsp;Lars Maegdefessel","doi":"10.1161/CIRCGENETICS.117.001859","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001859","url":null,"abstract":"Atherosclerosis progressively impairs functional integrity of the vasculature and, depending on which arteries are affected, can lead to a variety of serious complications. Roughly, one quarter of the Western population suffers from the consequences of carotid artery disease, such as a transient ischemic attack or stroke,1 which includes both neurological and cardiovascular complications. The atherosclerotic plaque, causing the narrowing in carotid arteries, can gradually evolve from a stable to an unstable lesion and ultimately rupture, causing an acute ischemic stroke. Several studies have shown that an early detection (<3 hours) of an acute ischemic stroke, followed by thrombolytic treatment, is associated with reduced mortality and symptomatic intracranial hemorrhage.2 Consequently, there is a great need for biomarkers that can support clinicians to follow and predict the progression of carotid artery disease toward an unstable, rupture-prone lesion.3 Capturing high-risk individuals who could benefit from an intensified therapy (including a surgical intervention such as carotid endarterectomies) is of eminent importance.\u0000\u0000See Article by Bazan et al \u0000\u0000Noncoding RNAs can be secreted by cells in a tissue-specific manner, either via passive leakage or via incorporation into subcellular particles.4 Because of the reported stability and detectability in the peripheral blood, they have recently received a lot of attention as attractive biomarkers.5 MiRNAs, with a size of ≈20 nucleotides, are the best-studied group of noncoding RNAs in cardiovascular disease development and progression, both from the biomarker, as well as the therapeutic perspective.6\u0000\u0000A more recent class of noncoding RNAs, circular RNA (circRNA), have emerged as promising biomarkers because of their intrinsic stability. …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001859","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35384205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}