TECRL is the causative gene of an autosomal-recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), the so-called type 3 CPVT. However, only 17 families have been reported worldwide and no case of symptomatic heterozygous carriers has been described. We report herein genotypes and clinical phenotypes of a family of European ancestry harboring a new TECRL pathogenic variant and, for the first time, a CPVT-like phenotype in a TECRL heterozygous variant carrier. Due to this novel evidence, clinicians should be aware that TECRL heterozygous variant carriers should undergo cardiac assessment and therapy introduction in case of a CPVT clinical diagnosis.

Since the first description of catecholaminergic polymorphic ventricular tachycardia (CPVT) in the 1970s, new insights have progressively unraveled the understanding of this inherited arrhythmia syndrome. The identification of new distinct clinical entities related to RYR2, the gene encoding the cardiac ryanodine receptor, has allowed significant refinement in the diagnosis of previously labeled “atypical” CPVT cases. Among RYR2-ryanodinopathies, the characterization of calcium release deficiency syndrome (CRDS) is still in its infancy and represents a diagnostic challenge due to the need for functional studies which may confirm the loss-of-function nature of the RYR2 variant. The present review summarizes current evidence on CRDS. First, by providing an overview on RYR2 structure and function, we will elucidate the different pathophysiological underpinnings of CRDS and CPVT. Second, by retrieving in detail reported CRDS variants and their clinical phenotypes, we will provide, if any, genetic and clinical red flags that should raise suspicion for CRDS in daily clinical practice. Finally, we will discuss available therapies to provide clinicians with practical therapeutic options for CRDS management.

Diamond-Blackfan anemia syndrome (DBA) is a ribosomopathy associated with loss-of-function variants in more than 20 ribosomal protein (RP) genes. Here, we report the genetic, functional, and biochemical dissection of 2 multigenerational pedigrees with variants in RPL17, a large ribosomal subunit protein-encoding gene. Affected individuals had clinical features and erythroid proliferation defects consistent with DBA. Further, RPL17/uL22 depletion resulted in anemia and micrognathia in zebrafish larvae, and in vivo complementation studies indicated that RPL17 variants were pathogenic. Lymphoblastoid cell lines (LCLs) derived from patients displayed a ribosomal RNA maturation defect reflecting haploinsufficiency of RPL17. The proteins encoded by RPL17 variants were not incorporated into ribosomes, but 10%-20% of 60S ribosomal subunits contained a short form of 5.8S rRNA (5.8S(C)), a species that is marginal in normal cells. These atypical 60S subunits were actively engaged in translation. Ribosome profiling showed changes of the translational profile, but those are similar to LCLs bearing RPS19 variants. These results link an additional RP gene to DBA. They show that ribosomes can be modified substantially by RPL17 haploinsufficiency but support the paradigm that translation alterations in DBA are primarily related to insufficient ribosome production rather than to changes in ribosome structure or composition.

Inherited cardiomyopathies and arrhythmias (ICAs) are a prevalent and clinically heterogeneous group of genetic disorders that are associated with increased risk of sudden cardiac death and heart failure. Making a genetic diagnosis can inform the management of patients and their at-risk relatives and, as such, molecular genetic testing is now considered an integral component of the clinical care pathway. However, ICAs are characterised by high genetic and allelic heterogeneity, incomplete / age-related penetrance, and variable expressivity. Therefore, despite our improved understanding of the genetic basis of these conditions, and significant technological advances over the past two decades, identifying and recognising the causative genotype remains challenging. As clinical genetic testing for ICAs becomes more widely available, it is increasingly important for clinical laboratories to consolidate existing knowledge and experience to inform and improve future practice. These recommendations have been compiled to help clinical laboratories navigate the challenges of ICAs and thereby facilitate best practice and consistency in genetic test provision for this group of disorders. General recommendations on internal and external quality control, referral, analysis, result interpretation, and reporting are described. Also included are appendices that provide specific information pertinent to genetic testing for hypertrophic, dilated, and arrhythmogenic right ventricular cardiomyopathies, long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND:Tetralogy of Fallot (TOF) is a rare, complex congenital heart defect caused by genetic and environmental interactions that results in abnormal heart development during the early stages of pregnancy. Genetic basis of TOF in Saudi populations is not yet studied. Therefore, the objective of this study is to screen for the molecular defects causing TOF in Saudi patients.METHODS:A family with non-syndromic TOF was recruited from the Western region of Saudi Arabia. Whole exome sequencing (WES) was performed on the proband and her parents. The identified candidate variant was verified by sanger sequencing. Also, different computational biology tools were used to figure out how candidate variants affect the structure and function of candidate protein involved in TOF.RESULTS:A novel heterozygous de novo mutation in LRP1 (p. G3311D) gene was identified in the index case. Also, this variant was absent in the in-house exome sequencing data of 80 healthy Saudi individuals. This variant was predicted to be likely pathogenic, as it negatively affects the biophysical chemical properties and stability of the protein. Furthermore, functional biology data from knock out mouse models confirms that molecular defects in LRP1 gene leads to cardiac defects and lethality. This variant was not previously reported in both Arab and global population genetic databases.CONCLUSION:The findings in this study postulate that the LRP1 variant has a role in TOF pathogenesis and facilitate accurate diagnosis as well as the understanding of underlying molecular mechanisms and pathophysiology of the disease.

This manuscript has conducted exome data analysis of the 200,643 UK Biobank individuals. They have sorted the likely pathogenic and pathogenic variants in the ACM, DCM and HCM associated genes. A prevalence of pathogenic variants have been identified like the below: ACM: 1:578; DCM: 1:251; HCM: 1: 149. Genotype positive individuals have increased mortality and morbidity, in particular for DCM and HCM variant carriers. This is not particularly true for ACM genotype positive carriers, though they have had significantly elevated risk of cardiac arryhthmia. I consider the manuscript is a very nice manuscript. It is well written and data are informative and has been arranged nicely. I have only three minor (may be major) comments:

HomeCirculation: Genomic and Precision MedicineVol. 15, No. 4Discordance Between Germline and Blood Mosaicism in Calmodulinopathy Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBDiscordance Between Germline and Blood Mosaicism in Calmodulinopathy Zahurul A. Bhuiyan, MBBS, PhD, Amnah Bdier, PhD, Jumana Y. Al-Aama, MD, Tatiana Abramova, MS and Alfred L. George Jr, MD Zahurul A. BhuiyanZahurul A. Bhuiyan Correspondence to: Zahurul A. Bhuiyan, MBBS, PhD, Division of Genetic Medicine, Lausanne University Hospital, BT.02.251, Av. de Beaumont 29, Lausanne CH-1011, Switzerland. Email E-mail Address: [email protected] https://orcid.org/0000-0003-2828-8870 Unité de Recherche Cardiogénétique, Service de Médecine Génétique, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (Z.A.B.). Search for more papers by this author , Amnah BdierAmnah Bdier Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders (A.B., J.Y.A.-A.), King Abdulaziz University, Jeddah, Saudi Arabia. Search for more papers by this author , Jumana Y. Al-AamaJumana Y. Al-Aama Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders (A.B., J.Y.A.-A.), King Abdulaziz University, Jeddah, Saudi Arabia. Department of Genetic Medicine, Faculty of Medicine (J.Y.A.-A.), King Abdulaziz University, Jeddah, Saudi Arabia. Search for more papers by this author , Tatiana AbramovaTatiana Abramova Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (T.A., A.L.G.). Search for more papers by this author and Alfred L. George JrAlfred L. George Jr https://orcid.org/0000-0002-3993-966X Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (T.A., A.L.G.). Search for more papers by this author Originally published11 May 2022https://doi.org/10.1161/CIRCGEN.121.003695Circulation: Genomic and Precision Medicine. 2022;15Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: May 11, 2022: Ahead of Print Pathogenic variants in each of the 3 genes (CALM1, CALM2, and CALM3) encoding the Ca2+ sensing protein calmodulin are associated with a life-threatening cardiac arrhythmia syndrome termed calmodulinopathy.1 The clinical presentation of calmodulinopathy is usually severe with neonatal and sometimes prenatal onset including fetal bradycardia, ventricular tachycardia/fibrillation, and cardiac arrest during infancy. The syndrome most often resembles congenital long-QT syndrome with an extremely prolonged QTc interval, episodes of T-wave alternans, and functional atrioventricular block but may also exhibit features of catecholaminergic polymorphic ventricular tachycardia. Heterozygous pathogenic calmodulin variants are most often de novo but may be inherited.We previously reported discovery of a novel CALM3 pathogenic variant (CALM3-D130G) in an Arab family, in which 5 of 6 offspring of healthy parents died between 10 days and 4.5 years of age (Figure [A]).2 We demonstrated heterozygous CALM3-p.Asp130Gly (D130G) in 2 siblings and recognized that the clinical phenotypes of the remaining 3 siblings who all had sudden cardiac deaths were consistent with calmodulinopathy.2 Furthermore, we assumed that the affected offspring for whom genotyping was not possible were also heterozygous for the pathogenic CALM3 variant. Conventional DNA sequencing did not detect the variant in DNA extracted from peripheral blood of either parent, but next-generation sequencing revealed the variant in 2.6% of reads in DNA from the father. Because the father was asymptomatic with a normal ECG (Figure [B]), we concluded that parental mosaicism explained the multiple affected offspring. Puzzled by the disproportionate number of affected offspring compared with the low rate (<3%) of mosaicism in the father’s blood DNA, we performed next-generation sequencing of DNA extracted from the father’s sperm. The data that support the findings of this study are available from the corresponding author upon reasonable request. Informed consent was obtained using a procedure approved by the Institutional Review Board of the King Abdulaziz University Faculty of Medicine, Jeddah, Saudi Arabia (reference: 417-10). This study revealed the pathogenic variant in 28.6% of next-generation sequencing reads from sperm DNA, which established gonosomal mosaicism in the father. Data from traditional Sanger DNA sequencing report an average of thousands of individual molecules and are not sensitive enough to detect differences in a small subset. Hence, low-level mosaicism is not reliably detected using this method. By contrast, data from next-generation sequencing report on thousands of individual molecules, and this enables greater sensitivity, as well as the opportunity to quantify subsets with variant nucleotide sequences. Although distinct sequencing technologies differ in sensitivity to detect mosaicism, the major reason for the observed discrepancy between blood and sperm DNA samples is likely intrinsic differences among tissues in the level of mosaicism.Download figureDownload PowerPointFigure. Males are represented as square symbols, females as circles. A, Pedigree of Saudi family with large number of sudden deaths among offspring. Males are represented as square symbols, and females as circles. CALM3 genotypes are given below each pedigree symbol where known. Individuals unavailable for genotyping are labeled as No DNA. B, Twelve lead ECG of the mosaic father (QTc, 438 ms).Furthermore, discordance in the proportion of a mosaic genotype between blood and sperm DNA is known to occur, and various mechanisms have been proposed to explain this phenomenon including clonal amplification of mutation-harboring spermatogonial cells as described for 2 common FGFR2 mutations.3 However, we remain puzzled by the disproportionate number of affected offspring (80%) compared with only 30% mutational load in sperm DNA. Interestingly, all reported cases of calmodulinopathy with overt familial occurrence were transmitted maternally.1We can speculate on potential mechanisms to explain greater success of paternal CALM3 variant transmission in this family. Calcium signaling in sperm is a central regulator of many key activities including motility and capacitation.4 Calmodulin is highly expressed in the testes, and calmodulin antagonists affect sperm motility and capacitation.5 The CALM3 variant could potentially confer a fertilization advantage through a cellular gain-of-function mechanism involving enhanced Ca2+ release from intracellular stores or entry through plasma membrane Ca2+ channels. Determining specific molecular mechanisms will require further study.In conclusion, data from our follow-up study of CALM3-D130G illustrate germline predominance over blood DNA that has significance for clinical geneticists in counseling patients with calmodulinopathy. Our finding may also promote reconsideration in cases with apparently de novo pathogenic calmodulin variants that might instead represent undetected mosaicism. Distinguishing true de novo mutations from occult mosaicism is critically important when providing reproductive counseling to families with calmodulinopathy and other life-threatening genetic arrhythmia syndromes.Article InformationSources of FundingThis work was supported, in part, by the American Heart Association grant 19SFRN34820006 (Dr George). Dr Bhuiyan was supported, in part, by the Swiss Heart Foundation grant (number 29283).Disclosures None.FootnotesFor Sources of Funding and Disclosures, see page 343.Correspondence to: Zahurul A. Bhuiyan, MBBS, PhD, Division of Genetic Medicine, Lausanne University Hospital, BT.02.251, Av. de Beaumont 29, Lausanne CH-1011, Switzerland. Email z.a.[email protected]chReferences1. Crotti L, Spazzolini C, Tester DJ, Ghidoni A, Baruteau AE, Beckmann BM, Behr ER, Bennett JS, Bezzina CR, Bhuiyan ZA, et al. Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International calmodulinopathy registry.Eur Heart J. 2019; 40:2964–2975. doi: 10.1093/eurheartj/ehz311CrossrefMedlineGoogle Scholar2. Wren LM, Jiménez-Jáimez J, Al-Ghamdi S, Al-Aama JY, Bdeir A, Al-Hassnan ZN, Kuan JL, Foo RY, Potet F, Johnson CN, et al. Genetic mosaicism in calmodulinopathy.Circ Genom Precis Med. 2019; 12:375–385. doi: 10.1161/CIRCGEN.119.002581LinkGoogle Scholar3. Goriely A, McVean GA, van Pelt AM, O’Rourke AW, Wall SA, de Rooij DG, Wilkie AO. Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia.Proc Natl Acad Sci USA. 2005; 102:6051–6056. doi: 10.1073/pnas.0500267102CrossrefMedlineGoogle Scholar4. Costello S, Michelangeli F, Nash K, Lefievre L, Morris J, Machado-Oliveira G, Barratt C, Kirkman-Brown J, Publicover S. Ca2+-stores in sperm: their identities and functions.Reproduction. 2009; 138:425–437. doi: 10.1530/REP-09-0134CrossrefMedlineGoogle Scholar5. Si Y, Olds-Clarke P. Evidence for the involvement of calmodulin in mouse sperm capacitation.Biol Reprod. 2000; 62:1231–1239. doi: 10.1095/biolreprod62.5.1231CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails August 2022Vol 15, Issue 4 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.121.003695PMID: 35543700 Originally publishedMay 11, 2022 Keywordsheart arrestdeath, sudden, cardiacgeneticsarrhythmias, cardiaccalmodulinPDF download Advertisement SubjectsGeneticsPrecision Medicine

MYBPC3 is the most frequently mutated gene in hypertrophic cardiomyopathy (HCM). Several loss-of-function founder variants have been reported in MYBPC3 from various geographic regions, altogether suggestive of a modest or absent effect of these variants on reproductive fitness. One of them, a MYBPC3 splice variant, NM_000256.3:c.3330+2T > G, was first described in homozygous state in newborns presenting with a severe, recessive form of HCM among the Amish population and was later associated with adult-onset dominant HCM in heterozygous carriers. We here report this splice variant in heterozygous state in eight unrelated Swiss families with HCM, making it the most prevalent cardiomyopathy variant in western Switzerland. This variant was identified in patients using targeted (n = 5) or full-genome sequencing (n = 3). Given the prevalence of this variant in the Old Order Amish, Mennonites and Swiss populations, and given that both Amish and Mennonites founders originated from the Bern Canton in Switzerland, the MYBPC3, NM_000256.3:c.3330+2T > G variant appears to be of Swiss origin. Neighboring regions that hosted the first Amish settlements (Alsace, South Germany) should be on the lookout for that variant. The existence of MYBPC3 founder variants in different populations suggests that individuals with early-onset clinical disease may be the tip of the iceberg of a much larger number of asymptomatic carriers. Alternatively, reproductive fitness could even be slightly increased in some variant carriers to compensate for the reduction of fitness in the more severely affected ones, but this remains to be investigated.

SCN5A overlap syndromes are clinical entities that express a phenotype combining aspects of different canonical SCN5A-related arrhythmia syndromes or a variable arrhythmic phenotype among individuals carrying the same SCN5A mutation. Here we review the literature addressing SCN5A overlap syndromes as well as the principal mechanisms currently proposed. Among others, a multifactorial determination encompassing an interaction between SCN5A variant(s), other genetic polymorphisms, and possibly environmental factors seems the most plausible hypothesis.

EDITORIAL article Front. Genet., 13 December 2021Sec. Genetics of Common and Rare Diseases Volume 12 - 2021 | https://doi.org/10.3389/fgene.2021.821591

Abstract not available Cardiovasc. j. 2021; 13(2): 106-111

Introduction: Sudden death and aborted sudden death have been observed in patients with biallelic variants in TECRL . Phenotypes have only begun to be described and no data are available on medical therapy after long-term follow-up. Methods: An international, multicenter retrospective review was conducted. We report new cases associated with TECRL variants and long-term follow-up from previously published cases. Results: We present 10 cases and 37 asymptomatic heterozygous carriers. Median age at onset of cardiac symptoms was 8 years (range 1-22 years) and cases were followed for an average of 10.3 years (SD 8.3), right censored by death in 3 cases. All patients on metoprolol, bisoprolol or atenolol were transitioned to nadolol or propranolol due to failure of therapy. Phenotypes typical of both long QT syndrome and catecholaminergic polymorphic ventricular tachycardia were observed. We also observed divergent phenotypes in some cases despite identical homozygous variants. None of 37 heterozygous family members had a cardiac phenotype. Conclusions: Patients with biallelic pathogenic TECRL variants present with variable cardiac arrhythmia phenotypes, including those typical of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia. Nadolol and propranolol may be superior beta-blockers in this setting. No cardiac disease or sudden death was present in patients with a heterozygous genotype.

Key Teaching Points•The variant p.Tyr473Cys in the ACTN2 gene, coding for the Z-disk protein alpha-actinin-2, leads to a dominantly inherited phenotype suggestive of left-dominant arrhythmogenic cardiomyopathy (ACM). This implies that analysis of ACTN2 might be considered in patients with ACM in whom genetic screening was inconclusive.•The signal for plakoglobin was markedly reduced in the myocardial biopsy of our index case. This further supports the concept that plakoglobin deficiency may be a common feature of ACMs, independently of their molecular origin.•The decreased signal for plakoglobin in the myocardial biopsy of our index case suggests a link between Z-disc proteins and the desmosome. This remains to be investigated. •The variant p.Tyr473Cys in the ACTN2 gene, coding for the Z-disk protein alpha-actinin-2, leads to a dominantly inherited phenotype suggestive of left-dominant arrhythmogenic cardiomyopathy (ACM). This implies that analysis of ACTN2 might be considered in patients with ACM in whom genetic screening was inconclusive.•The signal for plakoglobin was markedly reduced in the myocardial biopsy of our index case. This further supports the concept that plakoglobin deficiency may be a common feature of ACMs, independently of their molecular origin.•The decreased signal for plakoglobin in the myocardial biopsy of our index case suggests a link between Z-disc proteins and the desmosome. This remains to be investigated.

The gene SCN5A encodes the cardiac sodium channel which, through the conduction of Na+ current into the cell, generates the fast upstroke of the action potential of cardiomyocytes. Pathogenic variants of SCN5A have been causally associated to several hereditary cardiac diseases including, among others, Brugada syndrome, congenital long QT syndrome and sinus node dysfunction. Recently, overlap syndromes have been described that are characterized by the simultaneous expression of mixed clinical phenotypes among two or more hereditary cardiac diseases associated to the gene SCN5A (HCD-SCN5A). For this reason, it is time to rethink about HCD-SCN5A as different expressions of the same complex spectrum encompassing multiple clinical phenotypes with pronounced overlaps instead of as distinct clinical entities.

IntroductionAlström syndrome, ALMS (OMIM 203800) is a rare multi-systemic disease. The characteristic clinical features include blindness due to progressive cone-rod dystrophy, sensorineural hearing loss, type 2 diabetes mellitus, dilated cardiomyopathy, and childhood obesity. The aim of this study was to identify the genetic cause of Alström syndrome in patients who presented with variable clinical characteristics.Material and methodsClinical phenotyping and whole exome sequencing were performed in Saudi Alström syndrome patients. The Sanger sequencing was done to ascertain the segregation of Alström syndrome causative mutation in the family members. The rare prevalence of this mutation was further established by sequencing an additional 100 healthy Saudi controls.ResultsWhole exome sequencing analysis revealed that Alström syndrome patients have inherited a novel homozygous protein truncating mutation (c.2938dupA) in the ALMS1 gene segregated in an autosomal recessive fashion. This variant was absent in healthy controls. Genotype-phenotype analysis showed its interesting association with intra-familial clinical variability with regards to vision abnormalities, age at onset of dilated cardiomyopathy (DCM), obesity and hearing loss symptoms in the Alström syndrome patients.ConclusionsOur findings indicate that the atypical presentation of Alström syndrome, even within siblings, could sometimes lead to clinical misdiagnosis. Hence, the present study emphasizes the utility of exome sequencing to support the clinical diagnosis of Alström syndrome patients.

Dysfonction sinusale, syndrome de Brugada et syndrome du QT long chez un même patient Quand la génétique y perd son latin Le gène SCN5A code pour le canal sodique cardiaque qui est responsable de la pente de dépolarisation rapide du potentiel d'action.Plusieurs cardiopathies héréditaires (CH) ont été associées à des variants pathogènes du gène SCN5A incluant, entre autres, le syndrome de Brugada, le syndrome du QT long congénital et la dysfonction sinusale.Récemment, des syndromes de chevauchement ont été également décrits, s'exprimant, chez un même patient, par un phénotype clinique mixte comprenant une combinaison des manifestations rapportées ci-dessus.Dans ce contexte, nous devrions donc reconsidérer cliniquement les CH impliquant le gène SCN5A comme des expressions différentes d'un même éventail de phénotypes cliniques avec chevauchements marqués plutôt que comme des entités cliniques distinctes et isolées.Sinus node dysfunction, Brugada syndrome and long QT syndrome affecting the same patient : when genetics can't make head or tail of it The gene SCN5A encodes the cardiac sodium channel which, through the conduction of Na + current into the cell, generates the fast upstroke of the action potential of cardiomyocytes.Pathogenic variants of SCN5A have been causally associated to several hereditary cardiac diseases including, among others, Brugada syndrome, con genital long QT syndrome and sinus node dysfunction.Recently, overlap syndromes have been described that are characterized by the simultaneous expression of mixed clinical phenotypes among two or more hereditary cardiac diseases associated to the gene SCN5A (HCDSCN5A).For this reason, it is time to rethink about HCDSCN5A as different expressions of the same complex spectrum encompassing multiple clinical phenotypes with pronounced overlaps instead of as distinct clinical entities.

AIMS Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1-3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. METHODS AND RESULTS A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1-5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0-8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. CONCLUSION Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.