26 research outputs found
Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry
Calmodulin; Cardiomyopathies; Neurological disordersCalmodulina; Miocardiopatías; Trastornos neurológicosCalmodulina; Miocardiopaties; Trastorns neurològicsAims: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms.
Methods and results: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing.
Conclusion: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator.The ICalmR is one of the registries supported by ERN GUARD-Heart. This research was supported by the Italian Ministry of Health Ricerca Corrente ‘Registro internazionale delle calmodulinopatie’ to L.C., F.D., P.J.S., M.C.K., and C.S.; by the 2019-ATESP-0045 Fondo di Ateneo Quota Competitiva to L.C.; and partially by the Fondation Leducq grant 18CVD05 ‘Towards Precision Medicine with Human iPSCs for Cardiac Channelopathies’ to L.C., M.-C.K., L.S., and P.J.S. J.B., L.C., and P.J.S. were partially supported by the European Joint Programme on Rare Diseases: LQTS-NEXT grant. R.H. was supported by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, The Labatt Family Heart Centre, the Cartwright Family Fellowship, the Carter Heart Arrhythmia Trainee Fund and the Caitlin Elizabeth Morris fund. J.P.K. was supported by the Medical Research Council (MRC) Clinical Academic Research Partnership (CARP) Award (MR/T024062/1). G.R.W. was supported by an NIH K23HL130554 grant. A.A.M.W. was supported by the Netherlands Cardiovascular Research Initiative (CVON PREDICT-2). M.J.A. was supported in part by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. M.T.O. was supported in part by the Danish Independent Research Council (Grant no. 2032–00333B) and the Lundbeck Foundation (Grant no. R324-2019-1933). H.K.J. was supported by the Novo Nordisk Foundation (Grant NNF 18OC0031258)
Calmodulinopathy: Functional Effects of CALM Mutations and Their Relationship With Clinical Phenotypes
In spite of the widespread role of calmodulin (CaM) in cellular signaling, CaM mutations lead specifically to cardiac manifestations, characterized by remarkable electrical instability and a high incidence of sudden death at young age. Penetrance of the mutations is surprisingly high, thus postulating a high degree of functional dominance. According to the clinical patterns, arrhythmogenesis in CaM mutations can be attributed, in the majority of cases, to either prolonged repolarization (as in long-QT syndrome, LQTS phenotype), or to instability of the intracellular Ca2+ store (as in catecholamine-induced tachycardias, CPVT phenotype). This review discusses how mutations affect CaM signaling function and how this may relate to the distinct arrhythmia phenotypes/mechanisms observed in patients; this involves mechanistic interpretation of negative dominance and mutation-specific CaM-target interactions. Knowledge of the mechanisms involved may allow critical approach to clinical manifestations and aid in the development of therapeutic strategies for “calmodulinopathies,” a recently identified nosological entity
Genetics of Peripartum Cardiomyopathy: Current Knowledge, Future Directions and Clinical Implications
Peripartum cardiomyopathy (PPCM) is a condition in which heart failure and systolic
dysfunction occur late in pregnancy or within months following delivery. Over the last decade,
genetic advances in heritable cardiomyopathy have provided new insights into the role of genetics
in PPCM. In this review, we summarise current knowledge of the genetics of PPCM and potential
avenues for further research, including the role of molecular chaperone mutations in PPCM. Evidence
supporting a genetic basis for PPCM has emanated from observations of familial disease, overlap
with familial dilated cardiomyopathy, and sequencing studies of PPCM cohorts. Approximately
20% of PPCM patients screened for cardiomyopathy genes have an identified pathogenic mutation,
with TTN truncations most commonly implicated. As a stress-associated condition, PPCM may
be modulated by molecular chaperones such as heat shock proteins (Hsps). Recent studies have
led to the identification of Hsp mutations in a PPCM model, suggesting that variation in these
stress-response genes may contribute to PPCM pathogenesis. Although some Hsp genes have been
implicated in dilated cardiomyopathy, their roles in PPCM remain to be determined. Additional
areas of future investigation may include the delineation of genotype-phenotype correlations and the
screening of newly-identified cardiomyopathy genes for their roles in PPCM. Nevertheless, these
findings suggest that the construction of a family history may be advised in the management of
PPCM and that genetic testing should be considered. A better understanding of the genetics of PPCM
holds the potential to improve treatment, prognosis, and family management
Cadherin 2-Related Arrhythmogenic Cardiomyopathy Prevalence and Clinical Features
Background:Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the nondesmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM.Methods:A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of CDH2 was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of CDH2-positive probands, and clinical evaluation was performed.Results:Genetic screening of CDH2 led to the identification of 7 rare variants: 5, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in CDH2 were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most CDH2-positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and sudden cardiac death occurred in 5/9 (56%).Conclusions:In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with CDH2 pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of CDH2-ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.</p
Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry
AIMS: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. METHODS AND RESULTS: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. CONCLUSION: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator
Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.
PURPOSE: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. METHODS: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. RESULTS: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. CONCLUSION: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing
Genetic testing of patients with long QT syndrome and Brugada syndrome
Long QT syndrome (LQTS) and Brugada syndrome (BrS) are inherited cardiac
arrhythmias that may lead to sudden death in patients with structurally normal heart and
are characterized by variable penetrance and expressivity. Mutations in the genes of the
major cardiac K+ and Na+ channels are responsible for LQTS in 70% of cases, while
mutations of the Na+ cardiac channel gene are responsible for BrS in 20% of cases. The
genetic basis of these syndromes in the Greek population has not been previously
explored. We developed a uniform and efficient methodology for genetic testing of the
major cardiac ion channel genes my means of PCR-SSCP analysis and DNA sequencing
that was applied to patients with LQTS and BrS. In particular, we genetically screened 18
patients with a high, intermediate and low probability of LQTS and 15 patients with
definite or borderline diagnosis of BrS, based on clinical criteria. Genetic testing was
positive in 78% of patients with a high probability for LQTS and in 43% of patients with
a definite diagnosis of BrS. In LQTS, the majority of detected mutations have been
previously described and all belonged to types LQT1 and LQT2 of the syndrome, while
in BrS all detected mutations were novel. In addition, 28 single nucleotide
polymorphisms were detected, 6 of which are novel. Existing genotype-phenotype
correlations were successfully used to predict the genetic type in one case and were
thereafter found efficiently predictive of the genetic test results of the rest of the patients.
After the completion of genetic analysis of the probands, all family relatives that
consented were genetically screened. LQTS cascade family screening revealed 12
carriers among 17 relatives, 5 of which did not fulfill the criteria for a clinical diagnosis.
BrS cascade family screening revealed 7 carriers among 14 relatives, 5 of which did not
fulfill the criteria for a clinical diagnosis. All LQTS probands and relative carriers received β blocker treatment and have remained completely asymptomatic in 1-5 years
follow-up. Our results are in accordance with international data that genetic testing of the
major ion channel genes is efficient in genotyping the majority of LQTS patients with a
strong clinical diagnosis, while in BrS, genotyping efficiency was found higher than
expected. In total, the Greek genetic pool was found to differentiate, without significant
diversions. Genetic testing is a strong diagnostic tool for revealing subclinical and silent
forms of the syndromes in probands’ families, while identification of carrier status may
contribute substantially in patient management in terms of constant follow-up, risk
stratification and prophylactic measures and treatment.Το σύνδρομο μακρού QT (LQTS) και το σύνδρομο Brugada (BrS) είναι τα κληρονομικά
αρρυθμιογόνα νοσήματα που ενέχουν υψηλό κίνδυνο αιφνίδιου θανάτου σε έδαφος
δομικά φυσιολογικής καρδιάς και χαρακτηρίζονται από ποικίλη διεισδυτικότητα και
εκδηλωτικότητα. Μεταλλάξεις των κύριων γονιδίων των καρδιακών διαύλων ιόντων Κ+
και Na+ ευθύνονται για το LQTS στο 70% των περιπτώσεων, ενώ μεταλλάξεις του
γονιδίου του καρδιακού διαύλου ιόντων Na+ ευθύνονται για το BrS στο 20% των
περιπτώσεων. Η γενετική βάση των συνδρόμων αυτών στον ελληνικό πληθυσμό δεν έχει
προηγουμένως μελετηθεί. Αναπτύξαμε μία ενιαία και αξιόπιστη μεθοδολογία γενετικού
ελέγχου των κύριων γονιδίων των καρδιακών διαύλων με την μέθοδο PCR-SSCP και
αυτόματη ταυτοποίηση αλληλουχίας DNA, την οποία στη συνέχεια εφαρμόσαμε σε
ασθενείς με LQTS και BrS. Συγκεκριμένα, ελέγξαμε 18 ασθενείς με υψηλή, ενδιάμεση
και χαμηλή πιθανότητα LQTS και 15 ασθενείς με σαφή και οριακή διάγνωση BrS, βάσει
κλινικών κριτηρίων. Ο γενετικός έλεγχος απέβη θετικός στο 78% των ασθενών με υψηλή
πιθανότητα LQTS και στο 43% των ασθενών με σαφή διάγνωση BrS. Στο LQTS, οι
μεταλλάξεις που ανιχνεύθηκαν ανήκουν στους τύπους LQT1 και LQT2 και έχουν στην
πλειοψηφία τους περιγραφεί στην διεθνή βιβλιογραφία, ενώ στο BrS, ανιχνεύθηκαν νέες
μεταλλάξεις. Επιπλέον, ανιχνεύθηκαν 28 μονονουκλεοτιδικοί πολυμορφισμοί, 6 εκ των
οποίων φαίνεται έως σήμερα να ανήκουν αποκλειστικά στον ελληνικό πληθυσμό. Οι
κλινικογενετικές συσχετίσεις στο LQTS χρησιμοποιήθηκαν και προέβλεψαν επιτυχώς
τον γενετικό τύπο του συνδρόμου σε μία περίπτωση, ενώ εκ των υστέρων συσχετίστηκαν
καλά με τα αποτελέσματα του ελέγχου και των υπολοίπων ασθενών. Με την
ολοκλήρωση του γενετικού ελέγχου των ασθενών αναφοράς, όλοι οι συγγενείς τους που
συναίνεσαν να προσέλθουν, ελέγχθηκαν και αυτοί γενετικά. Κατά τον έλεγχο στην κατεύθυνση του LQTS, ταυτοποιήθηκαν 12 φορείς μεταξύ 17 συγγενών, 5 εκ των
οποίων χωρίς προϋποθέσεις σαφής κλινικής διάγνωσης. Κατά τον έλεγχο στην
κατεύθυνση του BrS, ταυτοποιήθηκαν 7 φορείς μεταξύ 14 συγγενών, 5 εκ των οποίων
χωρίς προϋποθέσεις κλινικής διάγνωσης. Οι ασθενείς αναφοράς με LQTS και όλοι οι
φορείς συγγενείς τους ξεκίνησαν θεραπεία με β αναστολείς και έχουν όλοι παραμείνει
ασυμπτωματικοί σε διάστημα 1-5 ετών παρακολούθησης. Τα αποτελέσματα μας είναι
σύμφωνα με τα διεθνή δεδομένα όπου ο έλεγχος των κύριων γονιδίων του LQTS είναι
ικανός να διαγνώσει γενετικά την πλειοψηφία των ασθενών με ισχυρή κλινική διάγνωση,
ενώ στην κατεύθυνση του BrS ο έλεγχος βρέθηκε αποδοτικότερος από το αναμενόμενο.
Στο σύνολο, η ελληνική γενετική δεξαμενή στα σύνδρομα αυτά φαίνεται να
διαφοροποιείται, αλλά δεν παρεκκλίνει σημαντικά. Ο γενετικός έλεγχος των οικογενειών
των ασθενών αναφοράς έχει ισχυρό διαγνωστικό ρόλο στις υποκλινικές και σιωπηλές
μορφές των συνδρόμων, ενώ η αναγνώριση των φορέων μπορεί να συνεισφέρει
σημαντικά στην διαχείριση τους σε επίπεδο συνεχούς παρακολούθησης,
διαστρωμάτωσης κινδύνου και προφυλακτικών μέτρων και θεραπείας
Phenotype reveals genotype in a Greek long QT syndrome family
We aimed to verify the tong QT syndrome (LQTS) genotype in a family with strong evidence of LQTS type 1 (LQT1) on the basis of so far established genotype-phenotype correlations. Genetic testing for mutations in the KCNQ1 potassium channel gene revealed an A341V mutation in three generations of the family. Existing genotype-phenotype correlations were correctly predictive of the genotype in the case of this family, despite the fact that there are no previously reported data for the Greek LQTS genetic pool. Thus, genotype-phenotype correlations are often a helpful tool in the management of LQTS patients and their families
Phenotype reveals genotype in a Greek long QT syndrome family
We aimed to verify the tong QT syndrome (LQTS) genotype in a family with
strong evidence of LQTS type 1 (LQT1) on the basis of so far established
genotype-phenotype correlations. Genetic testing for mutations in the
KCNQ1 potassium channel gene revealed an A341V mutation in three
generations of the family. Existing genotype-phenotype correlations were
correctly predictive of the genotype in the case of this family, despite
the fact that there are no previously reported data for the Greek LQTS
genetic pool. Thus, genotype-phenotype correlations are often a helpful
tool in the management of LQTS patients and their families