Genes frequently associated with sudden death in primary hypertrophic cardiomyopathy / Genes frecuentemente asociados con muerte súbita en miocardiopatía hipertrófica primaria

Abstract Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy without apparent cardiac justification. Sudden cardiac death may be the first manifestation of the disease. It occurs mainly in adulthood and can be seen in childhood and adolescence where genetic origin predominates. Primary HCM (“familial”) is inherited in an autosomal dominant pattern in the 25 subtypes informed in Online Mendelian Inheritance in Man. The proteins encoded by the mutated genes are part of the sarcomere in the cardiac cells, being the thick filament the most frequently affected, with the worst prognosis. In the present article, we describe the Mendelian inheritance of the disease and the two most associated genes with sudden death: MYBPC3 and MYH7.

Resumen La miocardiopatía hipertrófica (MCH) es el aumento de grosor de la pared ventricular izquierda no relacionada con otras alteraciones cardíacas. Es una enfermedad que puede presentar como primera manifestación clínica la muerte súbita y de ahí su relevancia clínica. Aunque se presenta sobre todo en la edad adulta, puede aparecer durante la infancia y adolescencia, en las que predominan los casos de origen hereditario. La MCH primaria, de causa genética, muestra en particular un patrón de herencia autosómico dominante en los 25 subtipos reconocidos en OMIM (Online Mendelian Inheritance in Man). Las proteínas codificadas por los genes mutantes forman parte del sarcómero en células musculares cardíacas, y las variantes patogénicas de filamentos gruesos son las de mayor frecuencia y peor pronóstico. En este artículo se describen la herencia mendeliana de la enfermedad y la relación con muerte súbita de los genes más frecuentemente encontrados en ella: MYBPC3 y MYH7.

Prenatal diagnosis and genetic analysis of a family with hypertrophic cardiomyopathy / 临床检验杂志

Objective@#To explore the relationship between HCM pathogenic gene mutations and clinical phenotypes by analyzing the prenatal diagnosis and genetic characteristics of a pregnant woman from a family with hypertrophic cardiomyopathy (HCM). @*Methods@#The clinical data of the proband and her family members was collected. The DNA was extracted from the peripheral blood, amniotic fluid cells and cultured amniotic fluid cells of proband. Next generation sequencing (NGS) was utilized for screening pathogenetic loci of the proband. The suspected mutation sequences of HCM pathogenic candidate genes MYH7 and MYBPC3 were directly sequenced after PCR. Pathogenicity prediction of amniotic fluid cells was performed by using genetic data and bioinformatics software, such as Mutation taster, PolyPhen-2 and ANTHEPROT. @*Results@#The sequencing results showed that heterozygous mutations of MYH7 c.1988G＞A (p.Arg663His) and MYBPC3 c.151G＞A (p.Ala51Thr) were found in the proband. The phenotype of her father was normal, and no abnormal mutations were detectable. Her mother also showed normal phenotype but carried MYBPC3 c.151G＞A heterozygous mutation. Only MYH7 c.1988G＞A heterozygous mutation was found in the fetus and no abnormal variation of MYBPC3 was showed. The prediction of mutation effect and analysis of protein structure and function revealed that the two missense mutations could affect the hydrophobicity and antigenicity of the protein. The genetic data demonstrated MYH7 c.1988G＞A was defined as a pathogenic mutation. @*Conclusion@#MYH7 c.1988G＞A should be a newly generated pathogenic mutation in the proband, or caused by reproductive chimerism of her parents. MYBPC3 c.151G＞A mutation may promote the occurrence of HCM. Although the fetus only carries MYH7 c.1988G＞A, her phenotype may still display as HCM.

Evaluation of a polymorphism in MYBPC3 in patients with anthracycline induced cardiotoxicity

Cardiotoxicity is the most serious side effect of anthracyclines (doxorubicin, daunorubicin or epirubicin). The incidence of anthracycline induced late cardiac toxicity (AIC) that is overt clinically is 3–5% in the Indian population. Polymorphism in intron 32 (deletion of 25 bp) of MYBPC3 has been shown to be present exclusively in Asians and more so in South India (3–8%). The frequency of the polymorphism is significantly higher (13%) in patients with cardiomyopathy in India. Fifteen patients were identified to have cardiac dysfunction following treatment for malignant lymphoma with doxorubicin containing regimens. Peripheral blood DNA from control, amplified by polymerase chain reaction yielded a 467 bp fragment while in the presence of the 25 bp deletion only a 442 bp fragment was detected. To confirm the presence or absence of the polymorphism, amplified DNA was restricted using Bgl1 in all samples. Bgl1 restricted amplified DNA only if the 25 bp deletion was absent. A 467 base pair band was observed in all the 15 samples, which suggested the absence of polymorphism in MYBPC3. In a sample of DNA from a patient with a deletion in exon 33 (confirmed by sequencing) a 442 bp fragment was detected. Amplified DNA from this patient was not restricted with Bgl1. Wild type MYBPC3 when amplified gave a distinct restriction banding pattern consisting of two bands of 401 bp and 66 bp. Amplified DNA from all peripheral blood samples restricted with Bgl1 suggesting the absence of the polymorphism. In this preliminary report, MYBPC3 does not seem to play a role in anthracycline induced cardiotoxicity.

The early diagnosis of MYH7 gene mutation carriers of hypertrophic cardiomyopathy using multi-parameter analysis model by conventional two-dimensional echocardiography and three-dimensional speckle tracking imaging / 中华超声影像学杂志

Objective To create multi-parameter analysis model by conventional two-dimensional echorcardiography( 2DE) and three-dimensional speckle tracking imaging( 3D-STI) in order to improve the early diagnosis in MYH7G + P- mutation carriers of familiar hypertrophic cardiomyopathy( HCM ) . Methods Twenty-eight MYH7 mutation carriers without left ventricular hypertrophy ( MYH7G + P- ) were enrolled as the research group , while 27 MYBPC3 mutation carriers without left ventricular hypertrophy ( MYBPC3G + P- ) were selected as the control group . The clinical data ,conventional 2DE and tissue Doppler imaging ( TDI) parameters of the two groups were acquired ,including the maximum of the thickness of interventricular septum( IVS) and left ventricular posterior ventricular wall thickness( LVPWT ) in end of diastole ,mitral flow E and A velocities ,E peak deceleration time( EDT ) ,atrioventricular filling time ,mitral annulus velocity of interventricular septum IVS-e' and lateral wall L-e' ,interventricular septum IVS-a' and lateral wall L-a' peak in diastole ,calculate mean value e' and a' ,and calculate E/ e' ,E/A ,left atrial volume index( LAVI) ,left ventricular mass index( LVMI) ,left ventricular ejection fraction( LVEF) and isovolumic relaxation time( IVRT ) ,isovolumic contraction time( IVCT ) . The global longitudinal peak strain( GLS) , global radial peak strain( GRS) ,global circumferential peak strain( GCS) and global area peak strain( GAS) were acquired by 3D-STI . All parameters were compared between research group and control group . Results Compared with the control group ,research group significantly increased in LAVI , maximum IVS and LVPWT ,LVMI and GAS( P < 0 .01) . There were no significant difference in TDI parameters( P > 0 .05) . For single parameter ,the area under ROC curve( AUC) were successively LVPWT > LAVI > IVS > LVMI >GAS( 0 .772 ,0 .738 ,0 .733 ,0 .719 ,0 .714 ,respectively) . AUC of multi-parameters was 0 .912 ,the sensitivity and specificity were 85 .2％ and 96 .3％ ,respectively . Conclusions Multi-parameter analysis model by conventional 2DE and 3D-STI can significantly improve the recognition efficiency of early diagnosis MYH7G + P- of familiar HCM . With further ,maximum LVPWT is an independent predictor of distinction MYH7G + P- and MYBPC3G + P- .

Myosin-binding Protein C Compound Heterozygous Variant Effect on the Phenotypic Expression of Hypertrophic Cardiomyopathy / Mutação em Hetrozigose Composta no Gene da Proteína C Ligante de Miosina e sua Expressão Fenotípica na Cardiomiopatia Hipertrófica

Abstract Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disease caused by mutations in genes encoding sarcomere proteins. It is the major cause of sudden cardiac death in young high-level athletes. Studies have demonstrated a poorer prognosis when associated with specific mutations. The association between HCM genotype and phenotype has been the subject of several studies since the discovery of the genetic nature of the disease. This study shows the effect of a MYBPC3 compound variant on the phenotypic HCM expression. A family in which a young man had a clinical diagnosis of HCM underwent clinical and genetic investigations. The coding regions of the MYH7, MYBPC3 and TNNT2 genes were sequenced and analyzed. The proband present a malignant manifestation of the disease, and is the only one to express HCM in his family. The genetic analysis through direct sequencing of the three main genes related to this disease identified a compound heterozygous variant (p.E542Q and p.D610H) in MYBPC3. A family analysis indicated that the p.E542Q and p.D610H alleles have paternal and maternal origin, respectively. No family member carrier of one of the variant alleles manifested clinical signs of HCM. We suggest that the MYBPC3-biallelic heterozygous expression of p.E542Q and p.D610H may cause the severe disease phenotype seen in the proband.

Resumo A cardiomiopatia hipertrófica (CMH) é uma doença autossômica dominante causada por mutações em genes que codificam as proteínas dos sarcômeros. É a principal causa de morte súbita cardíaca em atletas jovens de alto nível. Estudos têm demonstrado um pior prognóstico associado a mutações específicas. A associação entre genótipo e fenótipo em CMH tem sido objeto de diversos estudos desde a descoberta da origem genética dessa doença. Este trabalho apresenta o efeito de uma mutação composta em MYBPC3 na expressão fenotípica da CMH. Uma família na qual um jovem tem o diagnóstico clínico de CMH foi submetida à investigação clínica e genética. As regiões codificadoras dos genes MYH7, MYBPC3 e TNNT2 foram sequenciadas e analisadas. O probando apresenta uma manifestação maligna da doença e é o único em sua família a desenvolver CMH. A análise genética pelo sequenciamento direto dos três principais genes relacionados à essa doença identificou uma variante em heterozigose composta (p.E542Q e p.D610H) em MYBPC3. A análise da família mostrou que os alelos p.E542Q e p.D610H tem origem paterna e materna, respectivamente. Nenhum familiar portador de um dos alelos variantes manifestou sinais clínicos de CMH. Sugerimos que a expressão heterozigótica bialélica de p.E542Q e p.D610H pode ser responsável pelo fenótipo severo da doença encontrada no probando.