Alice Ghidoni

Long QT Syndrome–Associated Mutations in Intrauterine Fetal Death

IMPORTANCE Intrauterine fetal death or stillbirth occurs in approximately 1 out of every 160 pregnancies and accounts for 50% of all perinatal deaths. Postmortem evaluation fails to elucidate an underlying cause in many cases. Long QT syndrome (LQTS) may contribute to this problem. OBJECTIVE To determine the spectrum and prevalence of mutations in the 3 most common LQTS susceptible genes (KCNQ1, KCNH2, and SCN5A) for a cohort of unexplained cases. DESIGN, SETTING, AND PATIENTS In this case series, retrospective postmortem genetic testing was conducted on a convenience sample of 91 unexplained intrauterine fetal deaths (mean [SD] estimated gestational age at fetal death, 26.3 [8.7] weeks) that were collected from 2006-2012 by the Mayo Clinic, Rochester, Minnesota, or the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. More than 1300 ostensibly healthy individuals served as controls. In addition, publicly available exome databases were assessed for the general population frequency of identified genetic variants. MAIN OUTCOMES AND MEASURES Comprehensive mutational analyses of KCNQ1 (KV7.1, LQTS type 1), KCNH2 (HERG/KV11.1, LQTS type 2), and SCN5A (NaV1.5, LQTS type 3) were performed using denaturing high-performance liquid chromatography and direct DNA sequencing on genomic DNA extracted from decedent tissue. Functional analyses of novel mutations were performed using heterologous expression and patch-clamp recording. RESULTS The 3 putative LQTS susceptibility missense mutations (KCNQ1, p.A283T; KCNQ1, p.R397W; and KCNH2 [1b], p.R25W), with a heterozygous frequency of less than 0.05% in more than 10 000 publicly available exomes and absent in more than 1000 ethnically similar control patients, were discovered in 3 intrauterine fetal deaths (3.3% [95% CI, 0.68%-9.3%]). Both KV7.1-A283T (16-week male) and KV7.1-R397W (16-week female) mutations were associated with marked KV7.1 loss-of-function consistent with in utero LQTS type 1, whereas the HERG1b-R25W mutation (33.2-week male) exhibited a loss of function consistent with in utero LQTS type 2. In addition, 5 intrauterine fetal deaths hosted SCN5A rare nonsynonymous genetic variants (p.T220I, p.R1193Q, involving 2 cases, and p.P2006A, involving 2 cases) that conferred in vitro electrophysiological characteristics consistent with potentially proarrhythmic phenotypes. CONCLUSIONS AND RELEVANCE In this molecular genetic evaluation of 91 cases of intrauterine fetal death, missense mutations associated with LQTS susceptibility were discovered in 3 cases (3.3%) and overall, genetic variants leading to dysfunctional LQTS-associated ion channels in vitro were discovered in 8 cases (8.8%). These preliminary findings may provide insights into mechanisms of some cases of stillbirth.

The genetics underlying idiopathic ventricular fibrillation: A special role for catecholaminergic polymorphic ventricular tachycardia?

BACKGROUND Ventricular fibrillation (VF) is a major cause of sudden cardiac death. In some cases clinical investigations fail to identify the underlying cause and the event is classified as idiopathic (IVF). Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility, screening for disease-predisposing variants could improve IVF diagnostics. METHODS AND RESULTS The study included 76 Finnish and Italian patients with a mean age of 31.2years at the time of the VF event, collected between the years 1996-2016 and diagnosed with idiopathic, out-of-hospital VF. Using whole-exome sequencing (WES) and next-generation sequencing (NGS) approaches, we aimed to identify genetic variants potentially contributing to the life-threatening arrhythmias of these patients. Combining the results from the two study populations, we identified pathogenic or likely pathogenic variants residing in the RYR2, CACNA1C and DSP genes in 7 patients (9%). Most of them (5, 71%) were found in the RYR2 gene, associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). These genetic findings prompted clinical investigations leading to disease reclassification. Additionally, in 9 patients (11.8%) we detected 10 novel or extremely rare (MAF<0.005%) variants that were classified as of unknown significance (VUS). CONCLUSION The results of our study suggest that a subset of patients originally diagnosed with IVF may carry clinically-relevant variants in genes associated with cardiac channelopathies and cardiomyopathies. Although misclassification of other cardiac channelopathies as IVF appears rare, our findings indicate that the possibility of CPVT as the underlying disease entity should be carefully evaluated in IVF patients.

Desmoplakin missense and non-missense mutations in arrhythmogenic right ventricular cardiomyopathy: Genotype-phenotype correlation

BACKGROUND Arrhythmogenic right ventricular cardiomyopathy (ARVC) is traditionally considered as primarily affecting the right ventricle. Mutations in genes encoding desmosomal proteins account for 40-60% of cases. Genotype-phenotype correlations are scant and mostly non gene-specific. Accordingly, we assessed the genotype-phenotype correlation for desmoplakin (DSP) missense and non-missense mutations causing ARVC. METHODS AND RESULTS We analyzed 27 ARVC patients carrying a missense or a non-missense DSP mutation, with complete clinical assessment. The two groups were compared for clinical parameters, basic demographics such as sex, age at diagnosis, age at disease onset, as well as prevalence of symptoms and arrhythmic events. Missense DSP variants were present in 10 patients and non-missense in 17. Mean age at diagnosis and at first arrhythmic event did not differ between the two groups. Also the prevalence of symptoms, either major (60% vs 59%, p=1) or all (80% vs 88%, p=0.61), did not differ. By contrast, left ventricular (LV) dysfunction was significantly more prevalent among patients with non-missense mutations (76.5% vs 10%, p=0.001), who were also much more likely to have a structural LV involvement by Cardiac Magnetic Resonance (CMR) (92% vs 22%, p=0.001). CONCLUSIONS For ARVC patients, both missense and non-missense DSP mutations carry a high arrhythmic risk. Non-missense mutations are specifically associated with left-dominant forms. The presence of DSP non-missense mutations should alert to the likely development of LV dysfunction. These findings highlight the clinical relevance of genetic testing even after the clinical diagnosis of ARVC and the growing clinical impact of genetics.

Chemokines and Heart Disease: A Network Connecting Cardiovascular Biology to Immune and Autonomic Nervous Systems

Among the chemokines discovered to date, nineteen are presently considered to be relevant in heart disease and are involved in all stages of cardiovascular response to injury. Chemokines are interesting as biomarkers to predict risk of cardiovascular events in apparently healthy people and as possible therapeutic targets. Moreover, they could have a role as mediators of crosstalk between immune and cardiovascular system, since they seem to act as a “working-network” in deep linkage with the autonomic nervous system. In this paper we will describe the single chemokines more involved in heart diseases; then we will present a comprehensive perspective of them as a complex network connecting the cardiovascular system to both the immune and the autonomic nervous systems. Finally, some recent evidences indicating chemokines as a possible new tool to predict cardiovascular risk will be described.

Corrigendum to “Chemokines and Heart Disease: A Network Connecting Cardiovascular Biology to Immune and Autonomic Nervous Systems”

[This corrects the article DOI: 10.1155/2016/5902947.].

La sindrome del QT lungo nella morte improvvisa infantile: una malattia diagnosticabile e curabile

Nei paesi occidentali la sindrome della morte improvvisa infantile (SIDS) rappresenta la causa principale di morte nel primo anno di vita. Le ipotesi finora formulate sulla patogenesi della SIDS rimandano ad un quadro di tipo multifattoriale, in cui fattori di rischio diversi cooperano sinergicamente. Tra le possibili cause non cardiache, sono stati indagati diversi aspetti genetici tra i quali quelli legati a fattori immunitari, neuromodulatori ed enzimatici, che risultano tuttavia di difficile definizione sul piano clinico, soprattutto alla luce di possibili interventi terapeutici. Al contrario e possibile svolgere un’azione preventiva in quei potenziali casi SIDS, riconducibili ad aritmie cardiache su base genetica. Tra le canalopatie, la sindrome del QT lungo riveste un ruolo molto importante, essendo responsabile di circa il 10% dei casi SIDS. Un semplice elettrocardiogramma, eseguito nelle prime settimane dopo la nascita, consente di fare diagnosi di sindrome del QT lungo, individuando quindi i neonati a piu alto rischio aritmico per i quali e possibile iniziare una terapia beta-bloccate, efficace nella prevenzione delle aritmie maligne.