Long QT and short QT syndromes (LQTS and SQTS) are cardiac repolarization abnormalities that are characterized by length perturbations of the QT interval as measured on electrocardiogram (ECG). ...Prolonged QT interval and a propensity for ventricular tachycardia of the torsades de pointes (TdP) type are characteristic of LQTS, while SQTS is characterized by shortened QT interval with tall peaked T-waves and a propensity for atrial fibrillation. Both syndromes represent a high risk for syncope and sudden death. LQTS exists as a congenital genetic disease (cLQTS) with more than 700 mutations described in 12 genes (LQT1-12), but can also be acquired (aLQTS). The genetic forms of LQTS include Romano-Ward syndrome (RWS), which is characterized by isolated LQTS and an autosomal dominant pattern of inheritance, and syndromes with LQTS in association with other conditions. The latter includes Jervell and Lange-Nielsen syndrome (JLNS), Andersen syndrome (AS), and Timothy syndrome (TS). The genetics are further complicated by the occurrence of double and triple heterozygotes in LQTS and a considerable number of nonpathogenic rare polymorphisms in the involved genes. SQTS is a very rare condition, caused by mutations in five genes (SQTS1-5). The present mutation update is a comprehensive description of all known LQTS- and SQTS-associated mutations. Hum Mutat 30:1486-1511, 2009.
Brugada syndrome (BrS) is a condition characterized by a distinct ST-segment elevation in the right precordial leads of the electrocardiogram and, clinically, by an increased risk of cardiac ...arrhythmia and sudden death. The condition predominantly exhibits an autosomal dominant pattern of inheritance with an average prevalence of 5:10,000 worldwide. Currently, more than 100 mutations in seven genes have been associated with BrS. Loss-of-function mutations in SCN5A, which encodes the α-subunit of the Nav1.5 sodium ion channel conducting the depolarizing INa current, causes 15-20% of BrS cases. A few mutations have been described in GPD1L, which encodes glycerol-3-phosphate dehydrogenase-1 like protein; CACNA1C, which encodes the α-subunit of the Cav1.2 ion channel conducting the depolarizing IL,Ca current; CACNB2, which encodes the stimulating β2-subunit of the Cav1.2 ion channel; SCN1B and SCN3B, which, in the heart, encodes β-subunits of the Nav1.5 sodium ion channel, and KCNE3, which encodes the ancillary inhibitory β-subunit of several potassium channels including the Kv4.3 ion channel conducting the repolarizing potassium Ito current. BrS exhibits variable expressivity, reduced penetrance, and "mixed phenotypes," where families contain members with BrS as well as long QT syndrome, atrial fibrillation, short QT syndrome, conduction disease, or structural heart disease, have also been described. Hum Mutat 30:1-11, 2009.
Long-QT syndrome (LQTS), a cardiac arrhythmia disorder with variable phenotype, often results in devastating outcomes, including sudden cardiac death. Variable expression, independently from the ...primary disease-causing mutation, can partly be explained by genetic modifiers. This study investigates variants in a known LQTS-causative gene, AKAP9, for potential LQTS-type 1-modifying effects.
Members of a South African LQTS-type 1 founder population (181 noncarriers and 168 mutation carriers) carrying the identical-by-descent KCNQ1 p.Ala341Val (A341V) mutation were evaluated for modifying effects of AKAP9 variants on heart rate-corrected QT interval (QTc), cardiac events, and disease severity. Tag single nucleotide polymorphisms in AKAP9 rs11772585, rs7808587, rs2282972, and rs2961024 (order, 5'-3'positive strand) were genotyped. Associations between phenotypic traits and alleles, genotypes, and haplotypes were statistically assessed, adjusting for the degree of relatedness and confounding variables. The rs2961024 GG genotype, always represented by CGCG haplotype homozygotes, revealed an age-dependent heart rate-corrected QT interval increase (1% per additional 10 years) irrespective of A341V mutation status (P=0.006). The rs11772585 T allele, found uniquely in the TACT haplotype, more than doubled (218%) the risk of cardiac events (P=0.002) in the presence of A341V; additionally, it increased disease severity (P=0.025). The rs7808587 GG genotype was associated with a 74% increase in cardiac event risk (P=0.046), whereas the rs2282972 T allele, predominantly represented by the CATT haplotype, decreased risk by 53% (P=0.001).
AKAP9 has been identified as an LQTS-type 1-modifying gene. Variants investigated altered heart rate-corrected QT interval irrespective of mutation status, as well as cardiac event risk, and disease severity, in mutation carriers.
Sudden Death due to Troponin T Mutations Moolman, Johanna C; Corfield, Valerie A; Posen, Berthold ...
Journal of the American College of Cardiology,
03/1997, Volume:
29, Issue:
3
Journal Article
Peer reviewed
Open access
Objectives. This study was designed to verify initial observations of the clinical and prognostic features of hypertrophic cardiomyopathy caused by cardiac troponin T gene mutations.
Background. The ...most common cause of sudden cardiac death in the young is hypertrophic cardiomyopathy, which is usually familial. Mutations causing familial hypertrophic cardiomyopathy have been identified in a number of contractile protein genes, raising the possibility of genetic screening for subjects at risk. A previous report suggested that mutations in the cardiac troponin T gene were notable because they were associated with a particularly poor prognosis but only mild hypertrophy. Given the variability of some genotype:phenotype correlations, further analysis of cardiac troponin T mutations has been a priority.
Methods. Deoxyribonucleic acid from subjects with hypertrophic cardiomyopathy was screened for cardiac troponin T mutations using a ribonuclease protection assay. Polymerase chain reaction-based detection of a novel mutation was used to genotype members of two affected pedigrees. Gene carriers were examined by echocardiography and electrocardiology, and a family history was obtained.
Results. A novel cardiac troponin T gene mutation, arginine 92 tryptophan, was identified in 19 of 48 members of two affected pedigrees. The clinical phenotype was characterized by minimal hypertrophy (mean ±SD maximal ventricular wall thickness 11.3 ± 5.4 mm) and low disease penetrance by clinical criteria (40% by echocardiography) but a high incidence of sudden cardiac death (mean age 17 ± 9 years).
Conclusions. These data support the observation that apparently diverse cardiac troponin T gene mutations produce a consistent disease phenotype. Because this is one of poor prognosis, despite deceptively mild or undetectable hypertrophy, genotyping at this locus may be particularly informative in patient management and counseling.
(J Am Coll Cardiol 1997;29:549–55)
Abstract
Long QT syndrome (LQTS) is a genetic cardiac condition associated with prolonged ventricular repolarization, primarily a result of perturbations in cardiac ion channels, which predisposes ...individuals to life-threatening arrhythmias. Using DNA screening and sequencing methods, over 700 different LQTS-causing mutations have been identified in 13 genes worldwide. Despite this, the genetic cause of 30-50% of LQTS is presently unknown. MicroRNAs (miRNAs) are small (∼ 22 nucleotides) noncoding RNAs which post-transcriptionally regulate gene expression by binding complementary sequences within messenger RNAs (mRNAs). The human genome encodes over 1800 miRNAs, which target about 60% of human genes. Consequently, miRNAs are likely to regulate many complex processes in the body, indeed aberrant expression of various miRNA species has been implicated in numerous disease states, including cardiovascular diseases. MiR-1 and MiR-133A are the most abundant miRNAs in the heart and have both been reported to regulate cardiac ion channels. We hypothesized that, as a consequence of their role in regulating cardiac ion channels, genetic variation in the genes which encode MiR-1 and MiR-133A might explain some cases of LQTS. Four miRNA genes (miR-1-1, miR-1-2, miR-133a-1 and miR-133a-2), which encode MiR-1 and MiR-133A, were sequenced in 125 LQTS probands. No genetic variants were identified in miR-1-1 or miR-133a-1; but in miR-1-2 we identified a single substitution (n.100A> G) and in miR-133a-2 we identified two substitutions (n.−19G> A and n.98C> T). None of the variants affect the mature miRNA products. Our findings indicate that sequence variants of miR-1-1, miR-1-2, miR-133a-1 and miR-133a-2 are not a cause of LQTS in this cohort.
Comorbidity of certain obsessive-compulsive spectrum disorders (OCSDs; such as Tourette's disorder) in obsessive-compulsive disorder (OCD) may serve to define important OCD subtypes characterized by ...differing phenomenology and neurobiological mechanisms. Comorbidity of the putative OCSDs in OCD has, however, not often been systematically investigated.
The Structured Clinical Interview for
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I Disorders-Patient Version as well as a Structured Clinical Interview for Putative OCSDs (SCID-OCSD) were administered to 210 adult patients with OCD (N = 210, 102 men and 108 women; mean age, 35.7 ± 13.3). A subset of Caucasian subjects (with OCD, n = 171; control subjects, n = 168), including subjects from the genetically homogeneous Afrikaner population (with OCD, n = 77; control subjects, n = 144), was genotyped for polymorphisms in genes involved in monoamine function. Because the items of the SCID-OCSD are binary (present/absent), a cluster analysis (Ward's method) using the items of SCID-OCSD was conducted. The association of identified clusters with demographic variables (age, gender), clinical variables (age of onset, obsessive-compulsive symptom severity and dimensions, level of insight, temperament/character, treatment response), and monoaminergic genotypes was examined.
Cluster analysis of the OCSDs in our sample of patients with OCD identified 3 separate clusters at a 1.1 linkage distance level. The 3 clusters were named as follows: (1) “reward deficiency” (including trichotillomania, Tourette's disorder, pathological gambling, and hypersexual disorder), (2) “impulsivity” (including compulsive shopping, kleptomania, eating disorders, self-injury, and intermittent explosive disorder), and (3) “somatic” (including body dysmorphic disorder and hypochondriasis). Several significant associations were found between cluster scores and other variables; for example, cluster I scores were associated with earlier age of onset of OCD and the presence of tics, cluster II scores were associated with female gender and childhood emotional abuse, and cluster III scores were associated with less insight and with somatic obsessions and compulsions. However, none of these clusters were associated with any particular genetic variant.
Analysis of comorbid OCSDs in OCD suggested that these lie on a number of different dimensions. These dimensions are partially consistent with previous theoretical approaches taken toward classifying OCD spectrum disorders. The lack of genetic validation of these clusters in the present study may indicate the involvement of other, as yet untested, genes. Further genetic and cluster analyses of comorbid OCSDs in OCD may ultimately contribute to a better delineation of OCD endophenotypes.
Background: There is increasing recognition that obsessive–compulsive disorder (OCD) is not a homogeneous entity. It has been suggested that gender may contribute to the clinical and biological ...heterogeneity of OCD.
Methods: Two hundred and twenty patients (
n=220; 107 male, 113 female) with DSM-IV OCD (age: 36.40±13.46) underwent structured interviews. A subset of Caucasian subjects (
n=178), including subjects from the genetically homogeneous Afrikaner population (
n=81), and of matched control subjects (
n=161), was genotyped for polymorphisms in genes involved in monoamine function. Clinical and genetic data were statistically analyzed across gender.
Results: Compared with females, males with OCD (1) had an earlier age of onset, and a trend toward having more tics and worse outcome, (2) had somewhat differing patterns of OCD symptomatology and axis I comorbidity, and (3) in the Caucasian group, were more likely to have the high activity
T allele of the
EcoRV variant of the monoamine oxidase A (
MAO-A) gene compared to controls, and (4) in the Afrikaner subgroup, were more frequently homozygous for the
C allele at the
G861
C variant of the
5HT
1Dβ
gene than controls. Females with OCD (1) reported more sexual abuse during childhood than males, (2) often noted changes in obsessive–compulsive symptoms in the premenstrual/menstrual period as well as during/shortly after pregnancy, and with menopause, and (3) in the Caucasian subgroup, were more frequently homozygous for the low activity C allele of the
EcoRV variant of the
MAO-A gene compared to controls, with this allele also more frequent in female patients than controls.
Conclusion: This study supports the hypothesis that gender contributes to the clinical and biological heterogeneity of OCD. A sexually dimorphic pattern of genetic susceptibility to OCD may be present. Further work is, however, needed to delineate the mechanisms that are responsible for mediating the effects of gender.
Abnormal blood pressure response to exercise is reported to occur in up to a third of hypertrophic cardiomyopathy (HCM) cases and is associated with an increased risk of death, particularly in the ...young, but it is not known whether the HCM-causing mutation influences blood pressure response to exercise. The purpose of this article is to ascertain whether the blood pressure response to exercise differs among carriers of the R92W mutation in the cardiac troponin T gene (
TNNT2), which has been associated with an increased risk of sudden cardiac death in young males; carriers of mutations in the cardiac β-myosin heavy chain gene (
MYH7); and their noncarrier relatives. Thirty R92W
TNNT2
carriers, 51
MYH7 mutation carriers, and 68 of their noncarrier relatives were subjected to bicycle ergonometric exercise testing to assess blood pressure response to, as well as heart rate recovery after, exercise. Additional echocardiographic and demographic details were documented for all participants. R92W
TNNT2
carriers demonstrated significantly more abnormal blood pressure responses to exercise (
P = .021; odds ratio 3.03; confidence interval 1.13–8.12) and smaller increases in systolic blood pressure than
MYH7 mutation carriers or related noncarrier control individuals. Although abnormal blood pressure response occurred at similar frequencies in males in all groups (23%–26%), the percentage of R92W
TNNT2
females with abnormal blood pressure response was 64%, compared with 25% for
MYH7 and 22% for noncarriers. Therefore, these results show that blood pressure response to exercise is influenced by genotype and gender in patients with HCM.
There is increasing evidence that obsessive–compulsive disorder (OCD) is mediated by genetic factors. Although the precise mechanism of inheritance is unclear, recent evidence has pointed towards the ...involvement of the serotonergic and dopaminergic systems in the disorder's development. Furthermore, early-onset OCD appears to be a subtype that exhibits distinct clinical features and that is associated with greater familial loading. In the present investigation, South African OCD patients (
n=252) were stratified according to age of onset and were clinically assessed. Additionally, selected variants in genes encoding serotonergic and dopaminergic components were investigated in a Caucasian OCD subset (
n=180). This subgroup was further stratified to evaluate the role that these candidate genes may play in the genetically homogeneous Afrikaner subset (
n=80). Analysis of the clinical data revealed an association between early age of onset and an increased frequency of tics, Tourette's disorder, and trichotillomania (TTM). The genetic studies yielded statistically significant results when the allelic distributions of genetic variants in the dopamine receptor type 4 gene (
DRD4) were analysed in the Caucasian OCD cohort. These data support a role for the dopaminergic system, which may be relevant to the development of early-onset OCD.
A link between dissociation proneness in adulthood and self-reports of childhood traumatic events (including familial loss in childhood, sexual/physical abuse and neglect) has been documented. ...Several studies have also provided evidence for an association between dissociative experiences and trauma in patients with various psychiatric disorders, including post-traumatic stress disorder, borderline personality, dissociative identity and eating disorders. Based on the relative paucity of data on dissociation and trauma in obsessive-compulsive disorder (OCD) and trichotillomania (TTM), the primary objective of this study was to examine the relationship between trauma and dissociative experiences (DE) in these two diagnostic groups. Furthermore, the availability of clinical and genetic data on this sample allowed us to explore clinical and genetic factors relevant to this association. A total of 110 OCD and 32 TTM patients were compared with respect to the degree of dissociation (using the Dissociative Experiences Scale DES) and childhood trauma (using the Childhood Trauma Questionnaire CTQ). Patients were classified on the DES as either “high” (mean DES score ≥ 30) or “low” (mean DES score < 30) dissociators. Additional clinical and genetic factors were also explored with chi-square and
t tests as appropriate. A total of 15.8% of OCD patients and 18.8% of TTM patients were high dissociators. OCD and TTM groups were comparable on DES and CTQ total scores, and in both OCD and TTM groups, significant positive correlations were found between mean DES scores and mean CTQ subscores of emotional abuse, physical abuse, sexual abuse, and physical neglect. In the OCD group, high dissociators were significantly younger than low dissociators, and significantly more high dissociators than low dissociators reported a lifetime (current and past) history of tics (
P < .001), Tourette’s syndrome (
P = .019), bulimia nervosa (
P = .003), and borderline personality disorder (
P = .027). In the TTM group, significantly more high dissociators than low dissociators reported (lifetime) kleptomania (
P = .005) and depersonalisation disorder (
P = .005). In the Caucasian OCD patients (n = 114), investigation of genetic polymorphisms involved in monoamine function revealed no significant differences between high and low dissociator groups. This study demonstrates a link between childhood trauma and DE in patients with OCD and TTM. High dissociative symptomatology may be present in a substantial proportion of patients diagnosed with these disorders. High dissociators may also be differentiated from low dissociators on some demographic features (e.g., lower age) and comorbidity profile (e.g., increased incidence of impulse dyscontrol disorders). Additional work is necessary before conclusions about the role of monoaminergic systems in mediating such dissociation can be drawn.
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