Objectives This study aimed to identify the genetic defect in a family with idiopathic ventricular fibrillation (IVF) manifesting in childhood and adolescence. Background Although sudden cardiac ...death in the young is rare, it frequently presents as the first clinical manifestation of an underlying inherited arrhythmia syndrome. Gene discovery for IVF is important as it enables the identification of individuals at risk, because except for arrhythmia, IVF does not manifest with identifiable clinical abnormalities. Methods Exome sequencing was carried out on 2 family members who were both successfully resuscitated from a cardiac arrest. Results We characterized a family presenting with a history of ventricular fibrillation (VF) and sudden death without electrocardiographic or echocardiographic abnormalities at rest. Two siblings died suddenly at the ages of 9 and 10 years, and another 2 were resuscitated from out-of-hospital cardiac arrest with documented VF at ages 10 and 16 years, respectively. Exome sequencing identified a missense mutation affecting a highly conserved residue (p.F90L) in the CALM1 gene encoding calmodulin. This mutation was also carried by 1 of the siblings who died suddenly, from whom DNA was available. The mutation was present in the mother and in another sibling, both asymptomatic but displaying a marginally prolonged QT interval during exercise. Conclusions We identified a mutation in CALM1 underlying IVF manifesting in childhood and adolescence. The causality of the mutation is supported by previous studies demonstrating that F90 mediates the direct interaction of CaM with target peptides. Our approach highlights the utility of exome sequencing in uncovering the genetic defect even in families with a small number of affected individuals.
Brugada syndrome (BrS) is a common heritable channelopathy. Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most common genotype.
This study sought to perform a retrospective ...analysis of BrS databases from 9 centers that have each genotyped >100 unrelated cases of suspected BrS.
Mutational analysis of all 27 translated exons in SCN5A was performed. Mutation frequency, type, and localization were compared among cases and 1,300 ostensibly healthy volunteers including 649 white subjects and 651 nonwhite subjects (blacks, Asians, Hispanics, and others) that were genotyped previously.
A total of 2,111 unrelated patients (78% male, mean age 39 +/- 15 years) were referred for BrS genetic testing. Rare mutations/variants were more common among BrS cases than control subjects (438/2,111, 21% vs. 11/649, 1.7% white subjects and 31/651, 4.8% nonwhite subjects, respectively, P <10(-53)). The yield of BrS1 genetic testing ranged from 11% to 28% (P = .0017). Overall, 293 distinct mutations were identified in SCN5A: 193 missense, 32 nonsense, 38 frameshift, 21 splice-site, and 9 in-frame deletions/insertions. The 4 most frequent BrS1-associated mutations were E1784K (14x), F861WfsX90 (11x), D356N (8x), and G1408R (7x). Most mutations localized to the transmembrane-spanning regions.
This international consortium of BrS genetic testing centers has added 200 new BrS1-associated mutations to the public domain. Overall, 21% of BrS probands have mutations in SCN5A compared to the 2% to 5% background rate of rare variants reported in healthy control subjects. Additional studies drawing on the data presented here may help further distinguish pathogenic mutations from similarly rare but otherwise innocuous ones found in cases.
In sudden unexplained death (SUD) in the young (age 1-50 years), cardiologic and genetic examination in surviving relatives may unmask the cause of death in a significant proportion. The causes of ...aborted cardiac arrest (ACA) in this age group likely are similar to those in sudden cardiac death. However, there is a paucity of recent data on this topic.
The purpose of this study was to gain insight into the yield of current diagnostic strategies used in relatives of SUD victims and in ACA victims aged 1-50 years in our dedicated tertiary referral center.
We studied (1) all consecutive families who presented to the cardiology department for examination because of ≥1 first-degree related SUD victim aged 1-50 years and (2) all consecutive ACA victims aged 1-50 years who presented to the cardiology department from 1996 to 2009. Comprehensive cardiologic and genetic examination was performed in both populations.
A certain or probable diagnosis was made in 47 (33%) of 140 SUD families, including 45 (96%) cases of inherited cardiac diseases. Long QT syndrome (19%) was the most prevalent diagnosis. In 42 (61%) of 69 ACA victims, the cause of the event was determined (inherited in 31 74%). Hypertrophic cardiomyopathy was most prevalent (17%).
The yield of the current diagnostic workup in relatives of young SUD victims is 33% and is almost twice as high in young ACA victims. Inherited cardiac diseases are predominantly causative in both groups.
Objectives The purpose of this study was to investigate the follow-up and treatment of the mutation-carrying relatives of a proband with an inherited arrhythmia syndrome. Background The congenital ...long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) are primary inherited arrhythmia syndromes that may cause syncope and sudden cardiac death in young individuals. After establishing the disease-causing deoxyribonucleic acid (DNA) mutation in probands, we actively conducted cascade screening to identify, most often asymptomatic, relatives who are also at risk of life-threatening arrhythmias. Methods We retrospectively collected data from our cardiogenetics database and patient records and analyzed whether the identified carriers received prophylactic treatment. Results From 1996 to 2008, 130 probands with a disease-causing mutation in one of the involved genes were identified, and 509 relatives tested positive for the disease-causing familial mutation. These subjects subsequently underwent cardiologic investigation (electrocardiography, exercise testing, Holter monitoring, ajmaline testing, echocardiography, where appropriate). After a mean follow-up of 69 ± 31 months (LQTS), 60 ± 19 months (CPVT), and 56 ± 21 months (BrS), treatment was initiated and ongoing in 65% (199 of 308), 71% (85 of 120), and 6% (5 of 81) of the relatives in the LQTS, CPVT, and BrS families, respectively. Eight carriers were lost to follow-up. Treatment included drug treatment (n = 249) or implantation of pacemakers (n = 26) or cardioverter-defibrillators (n = 14). All mutation carriers received lifestyle instructions and a list of drugs to be avoided. Conclusions Cascade screening in families with LQTS, BrS, or CPVT, which was based on DNA mutation carrying and subsequent cardiologic investigation, resulted in immediate prophylactic treatment in a substantial proportion of carriers, although these proportions varied significantly between the different diseases.
Sudden unexplained death syndrome (SUDS) in young individuals often results from inherited cardiac disease. Accordingly, comprehensive examination in surviving first-degree relatives unmasks such ...disease in approximately 35% of the families. It is unknown whether individuals from diagnosis-negative families are at risk of developing manifest disease or cardiac events during follow-up.
This study aimed to study the prognosis of first-degree relatives of young SUDS victims, in whom the initial cardiologic and genetic examination did not lead to a diagnosis.
We retrieved vital status of surviving first-degree relatives from 83 diagnosis-negative families who presented to our cardiogenetics department between 1996 and 2009 because of SUDS in ≥1 relatives aged 1-50 years. Moreover, we contacted relatives who previously visited our center for detailed information.
We obtained detailed information (median follow-up 6.6 years; interquartile range 4.7-9.6 years) in 340 of 417 first-degree relatives (81.5%) from 77 of 83 families (92.8%). Vital status, available in 405 relatives (97.1%), showed that 20 relatives (4.9%) died during follow-up, including 1 natural death before the age of 50. This girl belonged to a family with multiple cases of idiopathic ventricular fibrillation and SUDS, including another successfully resuscitated sibling during follow-up. Two hundred thirty-four of 340 first-degree relatives (68.8%) underwent cardiologic examination. Of these, 76 (32.5%) were reevaluated. Inherited cardiac disease was diagnosed in 3 families (3.6%).
In first-degree relatives of young SUDS victims with no manifest abnormalities during the initial examination, the risk of developing manifest inherited cardiac disease or cardiac events during follow-up is low. This does not apply to families with obvious familial SUDS.
Considering that approximately 2% of Caucasian controls host rare, nonsynonymous variants in the SCN5A-encoded cardiac sodium channel, caution must be exercised when interpreting SCN5A genetic test ...results for long QT syndrome (LQTS).
The purpose of this study was to determine if A572D-SCN5A is a pathogenic mutation, a possible functional modifier, or background "genetic noise."
The frequency of A572D was compared between 3,741 LQTS referral cases (mostly Caucasian) and 1,437 Caucasian controls. A572D-SCN5A was engineered into SCN5A using the most commonly spliced transcript (Q1077del, hH1c clone) in the setting of either H558 or R558 for heterologous expression/patch clamp studies in HEK293 cells.
A572D-SCN5A was detected in 17 (0.45%) of 3,741 cases compared with 7 (0.49%) of 1,437 controls (P = .82). Among the 17 A572D-positive LQTS referrals, 10 (59%) hosted definite LQTS-causing mutations elsewhere (5 KCNQ1, 3 KCNH2, 2 SCN5A). Functional studies showed no gating kinetic or current density differences compared with wild-type channels in the context of H558 but showed moderate dysfunction when expressed in H558R-SCN5A, with which it is invariably associated.
There is sufficient evidence to conclude that A572D-SCN5A is not an independent, LQT3-causative mutation. A572D is present in approximately 0.5% of both cases and controls and has a wild-type phenotype when expressed in HEK293 cells. However, in the context of H558R-SCN5A, persistent late sodium current emerges, indicating that A572D/H558R could be a proarrhythmic factor akin to S1103Y. These findings underscore the scrutiny necessary to distinguish truly pathogenic mutations from functional polymorphisms and otherwise innocuous, rare genetic variants in SCN5A. These results also question how much cellular dysfunction for a mutation is required in vitro to support pathogenicity.
The Brugada syndrome is an inherited cardiac electrical disorder associated with a high incidence of life-threatening arrhythmias. Screening for mutations in the cardiac Na+ channel-encoding gene ...SCN5A uncovers a mutation in approximately 20% of Brugada syndrome cases. Genetic heterogeneity and/or undetected SCN5A mutations, such as exon duplications and deletions, could be involved in the remaining 80% mutation-negative patients.
Thirty-eight SCN5A mutation-negative Dutch Brugada syndrome probands were studied. The SCN5A gene was investigated for exon duplication and deletion, and a number of candidate genes (Caveolin-3, Irx-3, Irx-4, Irx-5, Irx-6, Plakoglobin, Plakophilin-2, SCN1B, SCN2B, SCN3B, and SCN4B) were tested for the occurrence of point mutations and small insertions/deletions.
We used a quantitative multiplex approach to determine SCN5A exon copy numbers. Mutation analysis of the candidate genes was performed by direct sequencing of polymerase chain reaction-amplified coding regions.
No large genomic rearrangements in SCN5A were identified. No mutations were found in the candidate genes. Twenty novel polymorphisms were identified in these genes.
Large genomic rearrangements in SCN5A are not a common cause of Brugada syndrome. Similarly, the studied candidate genes are unlikely to be major causal genes of Brugada syndrome. Further studies are required to identify other genes responsible for this syndrome.
Since his treatment, the clinical condition had improved. Because of Cryptosporidium parvum-related diarrhea, progressive lymphopenia, and failure to thrive, bone marrow transplantation was performed ...at the age of 8 years.
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