遗传病理临床进展课件

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,遗传病理学临床应用进展,遗传病理学临床应用进展,What is Disease,disease (d-zz,),n.,A pathological condition of a part, organ, or system of an organism resulting from various causes, such as infection, genetic defect, or environmental stress, and characterized by an identifiable group of signs or symptoms.,A condition or tendency, as of society, regarded as abnormal and harmful.,Obsolete.,Lack of ease,; trouble.,Part of your job is to build good experience in associating symptoms,and signs with disease names. This is an art and you have to be good,at it.,Once you become proficient, you will think:,What caused the disease? Endogenous reaction/defect or exogenous factor(s),How do I diagnose it,What is the molecular basis for the disease?,Why do diseases behave differently in different people?,What is Diseasedisease (d-z,精准医疗,精准医疗,Precision Medicine Initiative,Precision Medicine Initiative,遗传病理临床进展课件,遗传病理临床进展课件,Genome: Blueprint of life,Human Genome Project,Genome: Blueprint of life Hu,遗传病理临床进展课件,遗传病理临床进展课件,Research based upon the cohort data,Advance pharmacogenomics, the right drug for the right patient at the right dose,Identify new targets for treatment and prevention,Test whether mobile devices can encourage healthy behaviors,Lay scientific foundation for precision medicine for many diseases,Research based upon the cohort,Understanding,the Structure of,Genomes,Understanding,the Biology of,Genomes,Understanding,the Biology of,Disease,Advancing,the Science of,Medicine,Improving the,Effectiveness,of Healthcare,1990-2003,Human Genome Project,2004-2010,2011-2020,Beyond 2020,Genomic Accomplishments Across Domains,UnderstandingUnderstandingUnde,Courtesy from Eric Green, Director, NHGRI,Courtesy from Eric Green, Dire,外伤,遗传因素和环境因素在疾病中的作用,单基因疾病,多因子疾病,致病基因,易感基因,健康,/,疾病,=,基因,+,环境因素,基因,环境,血友病 大肠癌 老年痴呆 中风 心血管疾病 肺癌 交通意外,侏儒 乳腺癌 糖尿病 皮肤癌,哮喘,外伤遗传因素和环境因素在疾病中的作用单基因疾病多因子疾病致病,4/28/2013,3008,2761,247,1990,100,4/28/2013300827612471990 Hundreds of genetic cardiovascular diseases defined, 500 related genes identified, 200 (161+40),disease genes testable,Gene Testing of Cardiovascular,Cardiovascular Diseases,Hypertension,Hypertrophic cardiomyopathy,Cardiac arrhythmias,Lipoprotein disorders,Reactive oxygen species and atherosclerosis,Myocardial infarction,Acute coronary syndromes,Heart failure,Cardiac transplant rejection,Hemostasis and thrombosis,Peripheral arterial diseases,Congenital heart diseases,Perioperative and procedural medicine,Cardiovascular DiseasesHyperte,Cardiovascular Diseases,Hypertension,Hypertrophic cardiomyopathy,Cardiac arrhythmias,Lipoprotein disorders,Reactive oxygen species and atherosclerosis,Myocardial infarction,Acute coronary syndromes,Heart failure,Cardiac transplant rejection,Hemostasis and thrombosis,Peripheral arterial diseases,Congenital heart diseases,Perioperative and procedural medicine,Cardiovascular DiseasesHyperte,高血压病,缩压持续大于或等于,140,毫米汞柱，,舒张压持续大于或等于,90,毫米汞柱,。,临床表现：,轻者：头痛，头晕，头胀，颈部扳住感，耳鸣、眼花、健忘、失眠，烦闷，乏力，四肢麻木，心悸等。,严重者：会引起心力衰竭、脑溢血和肾功能衰竭等，甚至死亡。,高血压病 缩压持续大于或等于140毫米汞柱，,Hypertension,BP,Gene 2,+/-,Gene 3,+/-,Body mass,Age,Diet,sex,Environment,Gene 1,+/-,Susceptibility genes,Susceptibility genes,Susceptibility genes,Susceptibility genes,Susceptibility genes,HypertensionBPGene 2Gene 3Body,Rare Forms of Monogenic Hypertension,Liddle,s syndrome,Gordon,s syndrome,Glucocorticoid-remediable aldosteronism,Congenital adrenal hyperplasia,Rare Forms of Monogenic Hypert,Liddle,s syndrome,(pseudoaldosteronism),Autosomal dominant,hypertension associated with low plasma renin activity, metabolic alkalosis due to hypokalemia, and hypoaldosteronism (low secretion of aldosterone,醛固酮,).,one of several conditions known as pseudohyperaldosteronism.,begins in infancy.,abnormal kidney function, with excess reabsorption of sodium and loss of potassium from the renal tubule,caused by mutation at PPPxY motif of the beta or gamma subunit of an epithelial sodium channel (ENaC) gene at 16p13-p12 locus.,treated with a combination of low sodium diet and potassium-sparing diuretic drugs (e.g., amiloride).,Liddles syndrome(pseudoaldos,Gordon,s syndrome,(Type 2 pseudoaldosteronism),Symptoms: short stature, intellectual impairment, dental abnormalities, muscle weakness,severe hypertension,by the third decade of life, high blood potassium, hyperchloremic metabolic acidosis, low aldosterone level, low blood renin level, hypervolemia, hyperkalemia, normal renal function.,AD, mutations of,WNK1 and WNK4 (members of a family of serine-threonine kinases),gain of function and increased co-transporter activity, excessive chloride and sodium reabsorption, and volume expansion.,Rx: either a low-salt diet or thiazide diuretics, aimed at decreasing chloride intake and blocking Na-Cl co-transporter activity.,Gordons syndrome(Type 2 pseu,Glucocorticoid Remediable Aldosteronism, GRA (familial hyperaldosteronism type I),autosomal dominant, early onset of moderate to severe salt-sensitive form of low renin hypertension, persistent hyperaldosteronism, high incidence of premature cerebrovascular events. rapid suppression of aldosterone by exogenous glucocorticoid (dexamethasone) administration.,a chimeric gene is created by misalignment of chromatids and unequal crossing over between CYP11B1 (codes for 11-hydroxylase) and CYP11B2 (codes for aldosterone synthase), two genes that reside within a 30-kilobase stretch on chromosome 8.,the resulting chimeric gene encodes a protein that has aldosterone synthase enzymatic activity but is regulated by ACTH rather than angiotensin II.,Dx: both dexamethasone administration and genetic testing are of importance in making diagnosis.,Rx: glucocorticoids, sodium-restricted diet,Glucocorticoid Remediable Aldo,Congenital Adrenal Hyperplasia,Androgen excess and hypertension,11,b,-hydroxysteroid dehydrogenase mutated,Congenital Adrenal Hyperplasia,Hypertension,BP,Gene 2,+/-,Gene 3,+/-,Body mass,Age,Diet,sex,Environment,Gene 1,+/-,Susceptibility genes,Susceptibility genes,Susceptibility genes,Susceptibility genes,Susceptibility genes,HypertensionBPGene 2Gene 3Body,Hypertension,Predisposition,susceptibility genes (by association studies, 150, gene,”,in,“,bad environment,”,salt susceptibility, stress, climate, obesity,HypertensionPredisposition,Hypertension Susceptibility Genes,Apolipoproteins,Channels and Transporters,Cytoskeletal and Adhesion Molecules,Endothelins,Fat and Lipid Regulation,Glucose Regulation,Growth Factors and Hormones,Hypothalamus-Pituitary Axis,Intracellular Messengers,Kallikrein-Kinin pathway,Natriuretic Peptides,Renin-Angiotensin-Aldosterone pathway,Steroids,Sympathetic Nervous System,Thromboxanes and Prostaglandins,Miscellaneous,Hypertension Susceptibility Ge,Angiotensin II (Ang II) generated,in the afferent arteriole interacts,with AT,1,receptors on cellular,components of the nephron,Angiotensinogen,Ang I,Renin,ACE,Ang II,AT,1,R,= AT,1,Receptor,www.hypertensiononline.org,Angiotensin II (Ang II) genera,抗高血压药作用点,b,-Blockers,CCBs,*,Diuretics,ACE Inhibitors,AT,1,Blockers,a-Blockers,a,2,-Agonists,CCBs,DA,1,Agonists,Diuretics,Sympatholytics,Vasodilators,高血压,心脏输出量,外周血管阻力,www.hypertensiononline.org,=,X,* = non-dihydropyridine CCBs,抗高血压药作用点 b-BlockersACE Inhibi,Cardiovascular Diseases,Hypertension,Hypertrophic cardiomyopathy,Cardiac arrhythmias,Lipoprotein disorders,Reactive oxygen species and atherosclerosis,Myocardial infarction,Acute coronary syndromes,Heart failure,Cardiac transplant rejection,Hemostasis and thrombosis,Peripheral arterial diseases,Congenital heart diseases,Perioperative and procedural medicine,Cardiovascular DiseasesHyperte,恶性室性心律失常及心脏性猝死,SADS, or sudden arrhythmic death syndrome,恶性室性心律失常及心脏性猝死是心血管的重大疾病。 心肌离子通道基因突变（,long QT syndrome, Brugada syndrome,）和肥厚性心肌病,(,hypertrophic cardiomyopathy,),是导致恶性室性心律失常及心源性猝死的两种常见类型。,在美国，前者发病率约为,1/2000,，后者甚至更高达,1/500,。,我国目前尚缺乏恶性室性心律失常及心脏性猝死的详尽流行病学资料。恶性室性心律失常及心脏性猝死发病前往往症状不明显，普通临床手段不易检测，难以预防，猝死病人也常常无法确定真正原因，高危家庭成员无法有效预防。,恶性室性心律失常及心脏性猝死SADS, or sudden,Hank Gathers,(February 11, 1967 in Philadelphia March 4, 1990 in Los Angeles) Loyola Marymount,大学明星球员在全国直播的大学篮球联赛中因肥厚性心肌病死于赛场上,.,Hank Gathers(February 11, 1967,Sad History,Hank Gathers,Loyola Marymount star died March 4, 1990, after collapsing during West Coast Conference tournament semifinal game.,Reggie Lewis,Boston Celtics guard died July 27, 1993, while practicing at Brandeis University.,Conrad McRae,Former Syracuse University basketball player died July 10, 2000, while practicing with Orlando Magics entry in the Southern California Pro Summer League.,Anthony Bates,Kansas State football player died July 31, 2000, after suffering a heart attack during a car accident.,Thomas Herrion,San Francisco 49er died Aug. 20, 2005, after exhibition game in Denver.,Sad History Hank Gathers Loyol,肥厚性心肌病（,HCM,）临床特征,心肌原发性病变，表现心肌异常肥厚，左心室不能舒张，且不是因高血压或主动脉瓣肥厚。,HCM,组织学改变为心肌肥厚、心肌纤维排列紊乱。细胞与细胞之间的排列紊乱。大多数病人常症状不明显，只是在家族亲友普查时发现，,最常见症状：,(1),呼吸困难。,90%,有症状病人都有继发性左心室舒张功能紊乱、左室充盈障碍，左房、肺静脉压升高。,(2),心绞痛见于,75%,有症状病人。因心肌供氧与氧需求之间不平衡引起。,(3),昏厥：因劳累后心搏出量不足，或因心律失常。常见的心律失常有特发性房颤，非持续性室性心动过速等。猝死通常是青少年患者，暂无症状患者的首发症状，也是引起年轻运动员猝死最常见的原因。,HCM,呈现常染色体显性遗传，具有遗传异质性。发病率高达,1/500-1/1000,，是危害人们生命和健康的重大疾病。,肥厚性心肌病（ HCM ）临床特征心肌原发性病变，表现心肌异,HCM as a disease of the sarcomere,HCM as a disease of the sarcom,HCM Clinical Features,Left Ventricular Hypertrophy (LVH),Electrocardiograph (EKG) changes,Shortness of breath, chest pain, exercise intolerance,Increased risk of Sudden Cardiac Death (SCD),(variable, and may not occur in every patient),HCM Clinical FeaturesLeft Vent,Molecular Genetics of HCM,Autosomal dominant,The presence of a pathogenic mutation in one copy of the above listed genes is sufficient to cause HCM.,Children of an affected individual with an identified pathogenic mutation have a 50% risk of inheriting the same mutation.,Molecular Genetics of HCMAutos,Epidemiology of HCM,1/500 to 1/1000,Males and females are affected in equal frequency,No known racial predilection.,Epidemiology of HCM1/500 to 1/,Test Indications of HCM,Patients with clinical features of HCM.,Parents, siblings, and possibly children of a patient diagnosed with a mutation in one of the HCM genes.,Prenatal testing when a parent or child is diagnosed with HCM and has an identified sarcomere gene mutation.,Test Indications of HCMPatient,Test Outcomes of HCM,The detection of a pathogenic mutation will offer a definitive diagnosis for an affected patient.,Referral to a cardiology center with expertise in the management of hypertrophic cardiomyopathy is highly recommended.,Test Outcomes of HCMThe detect,Carrying a defect gene is not the end of the world,Eddie Curry, an NBA basketball player. Curry was with the Chicago Bulls, but he had two incidents of heart arrhythmia,Dr. David Cannom, at UCLA gave a green light,Carrying a defect gene is not,The NBA Is the First League to Begin Standardized Cardiac Screening,Filed under: News/Events - Posted on Sunday, September 17th, 2006 4:17 pm,The NBA Is the First League to,Center for Genetics & Genomics,Center for Genetics & Genomics,HCM,基因检测,HCM-A,HCM-B,HCM 基因检测 HCM-AHCM-B,HCM,基因检测,HCM-A:,MYH7, MYBPC3, TNNT2, TNNI3, TPM1,HCM-B:,ACTC, MYL2, MYL3,Unexplained Cardiac Hypertrophy (Danon disease, Glycogen storage cardiomyopathy):,LAMP2,and,PRKAG2,HCM 基因检测HCM-A: MYH7, MYBPC3, T,Cardiovascular Diseases,Hypertension,Hypertrophic cardiomyopathy,Ion channel related cardiac arrhythmias,Lipoprotein disorders,Reactive oxygen species and atherosclerosis,Myocardial infarction,Acute coronary syndromes,Heart failure,Cardiac transplant rejection,Hemostasis and thrombosis,Peripheral arterial diseases,Congenital heart diseases,Perioperative and procedural medicine,Cardiovascular DiseasesHyperte,长,QT,间期综合征,/BRUGADA,综合征等,突然失去知觉,(syncope),猝死,遗传性,(,1/,5,000),或后天药物诱发,正常,QT: 400 mSec,长,QT: 450 mSec,心脏电生理系统障碍,:,心跳后需要更长时间恢复,心电图,ECG (EKG),-,快速紊乱心律,(torsade de pointes),长QT间期综合征/BRUGADA综合征等 突然失去知觉,Autosomal Dominant (Romano-Ward Syndrome), Isolated susceptibility to ventricular arrhythmia, normal hearing,Autosomal Recessive (Jervell and Lange-Nielsen Syndrome), LQT plus sensorineural hearing loss,KvLQT1homozygous, compound heterozygous,KCNE1 (minK)homozygous,Genetics of Long QT Syndrome,Autosomal Dominant (Romano-War,Na,+,current,(LQT3, Brugada syndrome).,Transient outward K,+,current,Rapid component of delayed rectifier K,+,current,(LQT2 + LQT6),Slow component of the delayed rectifier K,+,current,(LQT1 + LQT5),Ultra-rapid component of the delayed rectifier K,+,current,L-type Ca,2+,current,Inwardly rectifying K,+,current,(Andersen syndrome),心肌跨膜电位,I,Na:,I,to:,I,Kur:,I,Kr:,I,Na,(I,Kur,),I,to,I,Kr,I,Ks,I,Ca(L),I,Kir,I,Ks:,I,Ca(L):,I,Kir:,Na+ current Transient outward,什么因素会诱发,LQTS?,Exercise,Emotional excitements,Sleep,Drugs,什么因素会诱发LQTS?ExerciseEmotional,LQTS,国际登记处和,罗切斯特大学遗传与基因组医学实验室,International LQTS Registry,- Established by Dr. Moss in 1979.,- To date, 1206 proband-identified families have been enrolled.,- Almost all important findings on LQTS directly came from or,collaborated with this registry.,LQTS Molecular Genetics Laboratory,-,Established in the Fall of 1999.,- ,2000,samples are collected and,mutational,- Many novel mutations have been identified.,-,Platform for genotype-phenotype co-,relationship studies, identification of new,LQT genes and modifier genes.,LQTS 国际登记处和 罗切斯特大学遗传与基因组医学实验室,LQTS Mutations by Type,(from Splawski et al Circulation, 2000. 102:1178),LQTS Mutations by Type(from Sp,LQTS Mutations by Position,(from Splawski et al Circulation, 2000. 102:1178),LQTS Mutations by Position(fro,Schematic of KvLQT1 and Locations of,LQT1-associated Mutations,Exon,No. of families,S2, S2/S3,S5, Pore,P, S6,S6, C-ter,(modified from Splawski et al Circulation, 2000. 102:1178),Position,S4/S5,Schematic of KvLQT1 and Locati,Schematic of HERG and Locations of LQT2-associated,Mutations,Exon,No. of families,(modified from Splawski et al Circulation, 2000. 102:1178),S5, P,S6,N-ter,cNBD,Position,Schematic of HERG and Location,Schematic of SCN5A and Locations of LQT3-associated,Mutations,No. of families,Exon,DIV/S3/S4/C-ter,DIII/DIV,(from Splawski et al Circulation, 2000. 102:1178),Position,Schematic of SCN5A and Locatio,Increased Risk of Arrhythmic Events in LQTS with Mutations,in the Pore Region of HERG Potassium Channel,(Moss et al, Circulation, 2002; 105:749),n= 34 (14 mutations),n= 91 (12 mutations),n= 54 (14 mutations),Increased Risk of Arrhythmic E,Reduced Penetrance of the LQTS, one study reported that 33% of clinically unaffected family members in kindreds containing a variety of LQTS mutations were found to be gene carriers .,(Priori, et al,Circulation, 1999. 99: 529),Reduced Penetrance of the LQTS,Molecular Genetics,of,Long QT Syndrome,And,Allelic Diseases,Molecular Genetics of Long Q,Disease Allelic to Long QT Syndrome 1,