RESUMO
BACKGROUND: Potentially lethal cardiac channelopathies/cardiomyopathies may underlie a substantial portion of sudden unexplained death in the young (SUDY). The whole-exome molecular autopsy represents the latest approach to postmortem genetic testing for SUDY. However, proper variant adjudication in the setting of SUDY can be challenging. METHODS: From January 2012 through December 2013, 25 consecutive cases of SUDY from 1 to 40 years of age (average age at death 27±5.7 years; 13 white, 12 black) from Cook County, Illinois, were referred after a negative (n=16) or equivocal (n=9) conventional autopsy. A whole-exome molecular autopsy with analysis of 99 sudden death-susceptibility genes was performed. The predicted pathogenicity of ultrarare, nonsynonymous variants was determined using the American College of Medical Genetics guidelines. RESULTS: Overall, 27 ultrarare nonsynonymous variants were seen in 16/25 (64%) victims of SUDY. Among black individuals, 9/12 (75%) had an ultrarare nonsynonymous variant compared with 7/13 (54%) white individuals. Of the 27 variants, 10 were considered pathogenic or likely pathogenic in 7/25 (28%) individuals in accordance with the American College of Medical Genetics guidelines. Pathogenic/likely pathogenic variants were identified in 5/16 (31%) of autopsy-negative cases and in 2/6 (33%) victims of SUDY with equivocal findings of cardiomyopathy. Overall, 6 pathogenic/likely pathogenic variants in 4/25 (16%) cases were congruent with the phenotypic findings at autopsy and therefore considered clinically actionable. CONCLUSIONS: Whole-exome molecular autopsy with gene-specific surveillance is an effective approach for the detection of potential pathogenic variants in SUDY cases. However, systematic variant adjudication is crucial to ensure accurate and proper care for surviving family members.
Assuntos
Autopsia/métodos , Canalopatias/genética , Canalopatias/mortalidade , Morte Súbita Cardíaca/epidemiologia , Sequenciamento do Exoma , Patologia Molecular , Adolescente , Adulto , Causas de Morte , Canalopatias/patologia , Morte Súbita Cardíaca/patologia , Feminino , Predisposição Genética para Doença , Humanos , Illinois/epidemiologia , Masculino , Fenótipo , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Fatores de Risco , Adulto JovemRESUMO
OBJECTIVES: This study determined if radical plakophilin-2 (PKP2) variants might underlie some cases of clinically diagnosed catecholaminergic polymorphic ventricular tachycardia (CPVT) and exercise-associated, autopsy-negative sudden unexplained death in the young (SUDY). BACKGROUND: Pathogenic variants in PKP2 cause arrhythmogenic right ventricular cardiomyopathy (ARVC). Recently, a cardiomyocyte-specific PKP2 knockout mouse model revealed that loss of PKP2 markedly reduced expression of genes critical in intracellular calcium handling. The mice with structurally normal hearts exhibited isoproterenol-triggered polymorphic ventricular arrhythmias that mimicked CPVT. METHODS: A PKP2 gene mutational analysis was performed on DNA from 18 unrelated patients (9 males; average age at diagnosis: 19.6 ± 12.8 years) clinically diagnosed with CPVT but who were RYR2-, CASQ2-, KCNJ2-, and TRDN-negative, and 19 decedents with SUDY during exercise (13 males; average age at death: 14 ± 3 years). Only radical (i.e., frame-shift, canonical splice site, or nonsense) variants with a minor allele frequency of ≤0.00005 in the genome aggregation database (gnomAD) were considered pathogenic. RESULTS: Radical PKP2 variants were identified in 5 of 18 (27.7%) CPVT patients and 1 of 19 (5.3%) exercise-related SUDY cases compared with 96 of 138,632 (0.069%) individuals in gnomAD (p = 3.1 × 10-13). Cardiac imaging or autopsy demonstrated a structurally normal heart in all patients at the time of their CPVT diagnosis or sudden death. CONCLUSIONS: Our data suggested that the progression of the PKP2-dependent electropathy can be independent of structural perturbations and can precipitate exercise-associated sudden cardiac arrest or sudden cardiac death before the presence of overt cardiomyopathy, which clinically mimics CPVT, similar to the PKP2 knockout mouse model. Thus, CPVT and SUDY genetic test panels should now include PKP2.
Assuntos
Morte Súbita Cardíaca/epidemiologia , Predisposição Genética para Doença , Placofilinas/genética , Taquicardia Ventricular , Adolescente , Adulto , Criança , Análise Mutacional de DNA , Exercício Físico , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Masculino , Taquicardia Ventricular/epidemiologia , Taquicardia Ventricular/genética , Adulto JovemRESUMO
The cone reconstruction technique, first described by da Silva and modified by Dearani and by others, has become the repair method of choice in patients with Ebstein anomaly of the tricuspid valve. This report details the outcome of the modified cone reconstruction technique in 6 children who underwent surgical correction of Ebstein anomaly at the Tomsk Institute of Cardiology in Siberia. From 2012 through 2015, 4 boys and 2 girls (age range, 11 mo-12 yr) underwent surgery to correct Ebstein anomaly. All had presented with cyanosis, exertional dyspnea, fatigue, or new-onset atrial arrhythmia, and none had undergone previous cardiac surgery. All survived the operation. One patient needed tricuspid valve replacement with a bioprosthesis after early breakdown of the cone reconstruction. As of December 2016, all the patients had no symptoms, tricuspid stenosis, or arrhythmia. This series indicates that cone reconstruction-the most anatomic repair technique for the dysmorphic Ebstein tricuspid valve-can be successfully performed in pediatric heart centers with a large experience.
Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Anomalia de Ebstein/cirurgia , Procedimentos de Cirurgia Plástica , Valva Tricúspide/cirurgia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Criança , Pré-Escolar , Anomalia de Ebstein/diagnóstico por imagem , Anomalia de Ebstein/fisiopatologia , Ecocardiografia Doppler em Cores , Feminino , Humanos , Lactente , Masculino , Procedimentos de Cirurgia Plástica/efeitos adversos , Recuperação de Função Fisiológica , Sibéria , Resultado do Tratamento , Valva Tricúspide/anormalidades , Valva Tricúspide/diagnóstico por imagem , Valva Tricúspide/fisiopatologiaRESUMO
Noonan syndrome (NS; MIM 163950) is an autosomal dominant disorder and a member of a family of developmental disorders termed "RASopathies," which are caused mainly by gain-of-function mutations in genes encoding RAS/MAPK signaling pathway proteins. Whole exome sequencing (WES) and trio-based genomic triangulation of a 15-year-old female with a clinical diagnosis of NS and concomitant cardiac hypertrophy and her unaffected parents identified a de novo variant in MRAS-encoded RAS-related protein 3 as the cause of her disease. Mutation analysis using in silico mutation prediction tools and molecular dynamics simulations predicted the identified variant, p.Gly23Val-MRAS, to be damaging to normal protein function and adversely affect effector interaction regions and the GTP-binding site. Subsequent ectopic expression experiments revealed a 40-fold increase in MRAS activation for p.Gly23Val-MRAS compared with WT-MRAS. Additional biochemical assays demonstrated enhanced activation of both RAS/MAPK pathway signaling and downstream gene expression in cells expressing p.Gly23Val-MRAS. Mutational analysis of MRAS in a cohort of 109 unrelated patients with phenotype-positive/genotype-negative NS and cardiac hypertrophy yielded another patient with a sporadic de novo MRAS variant (p.Thr68Ile, c.203C>T). Herein, we describe the discovery of mutations in MRAS in patients with NS and cardiac hypertrophy, establishing MRAS as the newest NS with cardiac hypertrophy-susceptibility gene.
Assuntos
Cardiomegalia/genética , Genes ras , Síndrome de Noonan/genética , Adolescente , Adulto , Sequência de Aminoácidos , Cardiomegalia/complicações , Criança , Pré-Escolar , Feminino , Células HEK293 , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Simulação de Dinâmica Molecular , Síndrome de Noonan/complicações , Homologia de Sequência de Aminoácidos , Sequenciamento do Exoma , Adulto JovemRESUMO
OBJECTIVE: To use whole exome sequencing (WES) of a family trio to identify a genetic cause for polyvalvular syndrome. METHODS AND RESULTS: A male child was born with mild pulmonary valve stenosis and mild aortic root dilatation, and an atrial septal defect, ventricular septal defect, and patent ductus arteriosus that were closed surgically. Subsequently, the phenotype of polyvalvular syndrome with involvement of both semilunar and both atrioventricular valves emerged. His family history was negative for congenital heart disease. Because of hypotonia, myopia, soft pale skin, joint hypermobility, and mild facial dysmorphism, either Noonan syndrome- or William syndrome-spectrum disorders were suspected clinically. However, chromosomal analysis was normal and commercially available Noonan syndrome and William syndrome genetic tests were negative. Whole exome sequencing of the patient and both parents was performed. Variants were analyzed by sporadic and autosomal recessive inheritance models. A sporadic mutation, annotated as c.1491 T > A, in TAB2, resulting in a nonsense mutation, p.Y497X, in the TAB2-encoded TGF-beta activated kinase 1 (TAK1) was identified as the most likely disease-susceptibility gene. This mutation results in elimination of the terminal 197 amino acids, including the C-terminal binding motif critical for interactions with TRAF6 and TAK1. CONCLUSIONS: The combination of WES, genomic triangulation, and systems biology has uncovered perturbations in TGF-beta activated kinase 1 signaling as a novel pathogenic substrate for polyvalvular syndrome.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Códon sem Sentido , DNA/genética , Sequenciamento do Exoma/métodos , Doenças das Valvas Cardíacas/genética , Metagenômica/métodos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Análise Mutacional de DNA , Seguimentos , Previsões , Doenças das Valvas Cardíacas/congênito , Doenças das Valvas Cardíacas/enzimologia , Humanos , Recém-Nascido , Masculino , Linhagem , SíndromeRESUMO
We illustrate the work necessary to reverse course after identification of a KCNQ1 variant interpreted erroneously as causing long QT syndrome (LQTS) and to identify the true cause of a case of sudden death in the young. Surrogate genetic testing of a decedent's living brother identified a rare KCNQ1-V133I variant, which prompted an implantable cardioverter defibrillator and subsequent diagnosis of LQTS in other family members. Subsequently, this presumed LQT1 family came to our institution for further clinical evaluation and research-based investigations, including KCNQ1-V133I variant-specific analysis of the decedent, heterologous expression studies of KCNQ1-V133I, and a whole-exome molecular autopsy along with genomic triangulation using his unaffected parents' DNA. After evaluating several V133I-positive family members, clinical doubt was cast on the veracity of the previously levied diagnosis of LQT1, resulting in a re-opening of the case and an intense pursuit of the lethal substrate. Furthermore, the decedent tested negative for V133I, and heterologous expression studies demonstrated a normal cellular phenotype for V133I-containing Kv7.1 channels. Instead, after whole-exome molecular autopsy, a de novo pathogenic variant (p.R454W) in DES-encoded desmin was identified. As detailed herein, the forensic evaluation of sudden death in the young requires meticulous focus on the decedent followed by a careful and deliberate assessment of the decedent's relatives. Surrogate genetic testing can have disastrous consequences and should be avoided. Genetic test results require careful scrutiny to avoid unintended and potentially devastating repercussions. Although the root cause of the decedent's tragic death would have remained a mystery, the unintended consequences for the living relatives described herein might have been avoided based on clinical grounds alone. All family members had electrocardiograms with normal QT intervals, making the diagnosis of familial LQTS unlikely. As such, if the clinicians caring for these patients had focused solely on clinical data from the survivors, there might have been no reason to embark on a path of inappropriate treatment based on genetic testing.