单基因遗传病ppt课件

,单基因遗传病,Basic Conception,Dominant A,Homozygote AA or aa,Heterozygote Aa,Recessive a,Whats Monogenic Disorders?,The diseases that are the result of a single mutant gene that has a large effect on phenotype and that are inherited in simple patterns similar to or identical with those described by Mendel for certain discrete characteristics in garden peas.,The Basic Patterns of Single Gene Inheritance,Autosomal Dominant Autosomal Recessive X-linked Dominant X-linked Recessive Y-linked Inheritance,OMIM Statistics for Sept. 13, 2005,Autosomal 15212X-linked 906Y-linked 56Mitochondrial 6216236,/Omim/mimstats.html,PEDIGREES :They are graphic representations of a family tree which show the biological relationship of the index case, or proband or propositus(先证者) to the rest of the individuals.,Symbols are used to illustrate the various states and relationships of the family tree.,常染色体显性遗传Autosomal Dominant Inheritance,AD diseases are those in which a single copy of a mutant gene on autosome is enough for the trait to be expressed or shown.,Autosomal Dominant (AD),婚配类型和子代发病风险,Pedigree Characteristics,Aa,aa,Each affected individual has one affected parent,50 % of offspring are affected,Males and females are affected with equal probability,Passed in a vertical fashion,Pedigree Characteristics,系谱特征,1.遗传与性别无关，男女受累的机会均等2.患者父母必有一方受累3.每代都可出现患者，在连续世代中呈垂直分布。偶尔由于外显不足而出现隔代遗传的现象4.双亲无病时，子代一般均正常(除非新的基因突变), 3040岁发病，也有10多岁或60 岁以后发病 有进行性不自主的舞蹈样动作，可合并肌强直 可出现神经症状，如抑郁，智能衰退，最终成为痴呆,Huntington 舞蹈症 Huntingtons chorea,Mechanism of the Disorder, HD 基因位于4p16.3，致病基因编码区IT15 5 端具有(CAG)n 三核苷酸重复。正常人 934次，患者重复37100次。且 CAG 重复的多少与疾病的早晚、严重程度成正比。有遗传印记或早现（genetic imprinting or anticipation）现象,Pathobiology Change,CLINICAL EXAMPLES,Familial hypercholesterolemia (家族性高胆固醇血症)Polysystic kidney disease,adult (成年多囊肾病) Alpha- thalassemias (-地中海贫血) Brachydactyly, type A1 短指(趾)症A1型 Neurofibromatosis, type 1 (神经纤维瘤),常染色体隐性遗传Autosomal Recessive Inheritance,Pedigree Characteristics,Both parents are carriers,The diseases are sporadic,The risk of offspring is higher in consanguineous marriage,1/4 of sibs are affected. Males and females are affected with equal probability,Pedigree Characteristics,2/3 of unaffected sibs are carriers,遗传与性别无关，男女受累的机会均等。患者为隐性基因纯合子，父母表现正常，但均为致病基因携带者。系谱中无连续遗传现象，常为散发或隔代遗传。近亲婚配的后代中发病率显著增高。,系谱特征,CLINICAL EXAMPLES,Albinism (白化症)Galactosaemia (半乳糖血症) Homocystinuria (高光氨酸尿症) Cystic fibrosis (囊性纤维化) Sickle cell anaemia (镰刀型细胞贫血) Thalassemias (地中海贫血) Phenylketonuria (苯丙酮酸尿症),X 连锁的显性遗传X-linked Dominant Inheritance,Pedigree Characteristics,The ratio of affected females to the males is approximately 2 to 1,Each affected individual has one affected parent,All daughters of affected males are affected, all sons of affected males are normal; 50% offspring of affected female have chance of being affected,Passed in a vertical fashion,Pedigree Characteristics,1.致病基因在X染色体上，患者父母中必有一方为受累者。2.每代都可出现患者，象AD那样垂直分布。3.女性患者的子女中1/2为患者，男性患者只将疾病传给女儿。4.女性患者多于男性，且临床症状较轻。女性杂合子患者常流产。,系谱特征,抗维生素D性佝偻病（Vitamin D resistant rickets） 低磷酸盐血症，血清磷下降50%，尿磷增多。 男性严重，下肢出现畸形，女性骨骼畸形多不严重；一周岁发病，开始为型腿表现。 大剂量 VitD 不能纠正发育异常。 肾小管对磷的重吸收降低引起。 致病基因 PHEX 位于 Xp22。,Clinical Example,Vitamin D Resistant Rickets,Vitamin D Resistant Rickets (MIM 307800),X 连锁的隐性遗传X-linked Recessive Inheritance,Pedigree Characteristics,More affected males than affected females,Each son has 50% chance of being affected, each daughter has 50% chance of being a carrier,Because of criss-cross inheritance, brothers, sons of mothers sisters, brothers of mother, sons of sisters of affected individual have chance of being affected,Passed with female carriers,Pedigree Characteristics,1.致病基因位于X染色体上，男性患者显著多于女性患者。2. 呈交叉遗传。男性患者把致病基因通过杂合子女儿传给他们半数的儿子，可出现隔代遗传现象。3.携带者女性与正常男性婚配，男孩每胎得病概率为0.5。男性患者与正常女性婚配，子女都正常，女孩必为携带者。4.家系中患者呈斜行分布，舅父和外甥受累。男性患者决不把此病传给儿子。,系谱特征,CLINICAL EXAMPLES,色盲眼白化病无丙种球蛋白血症G- 6 - PD 缺乏症肾性尿崩症血友病 B睾丸女性化,先天性高尿酸血症粘多糖累积症 型肌营养不良症（Becker 型、 Duchenne 型 )慢性肉芽肿病无汗型外胚层发育不良症,Duchenne 型肌营养不良症临床表现： 1.进行性肌营养不良 2.腓肠肌假性肥大 3.下肢无力，行走呈鸭行 步态 4.仰卧位起立出现Gower征病因：抗肌萎缩蛋白遗传性缺陷,Familial：X-linked recessive (MIM 306700),Chromosome: Xq28 Gene: coagulation factor VIIIc,Hemophilia A,Hemophilia A,Y连锁遗传(Y-linked inheritance),决定某种性状或疾病的基因位于Y染色体上，只要Y染色体上有此基因，即可表现出相应的性状。系谱特征： 具有Y连锁者均为男性，亲代男方携带此基因只传给全部儿子，不传给女儿，即男-男传递(male to male transmission)。,影响单基因遗传病分析的一些问题,一、外显率 (Reduced penetrance ),It is a clinical term which is an expression of the number of individuals who have the gene and show the trait. It is an all or nothing phenomenon and if the frequency is less than 100 %, reduced penetrance exists.外显率 : 指在一个有致病基因（显性杂合或者隐性纯合）的群体中得以表现的百分率。完全外显 100%,不完全外显 100 %,顿挫型:未外显。,二、表现度（ Variable expressivity ）,It refers to the degree of expression of a trait. The individuals in a family may show mild to moderate to severe forms of the disease and need to be examined carefully in order not to miss the diagnosis. 表现度:指一种致病基因的表达程度，与外显率是质与量的关系。轻度(mild)、中度(moderate)、重度(severe)。,指一个基因可以决定或影响多个性状。,三、基因多效性 ( pleiotropy ),四、遗传异质性(genetic heterogeneity),Here a similar clinical picture may be produced by different mutations at the same locus or at different loci. Retinitis pigmentosa may be caused by both autosomal dominant or recessive inheritance. 遗传异质性: 是指一种性状可以有多个不同的基因控制。由于遗传基础的不同，它们的遗传方式 、发病年龄、病情进展、严重程度、受损部位、预后以及复发率等等，都可能是不同的。例如智能发育不全。,五、遗传印迹 (Genetic Imprinting ),Variation in severity dependent on sex .In Huntingtons disease the disease manifests earlier, if the affected parent is the father.遗传印迹：指同一基因会随着它来自父源或母源而有不同的表现。这与基因在生殖细胞形成的过程中受到不同的修饰有关，一些遗传病的表现度与外显率就受到突变基因遗传印迹的影响。,六、延迟显性 (delayed dominance),Variation in age onset： Adult polycystic kidney disease although inherited as a dominant trait shows cysts only later in life. 延迟显性 ：带有显性基因的个体有时在早年并不表现症状体征，而到成年才发病。,指一些遗传病（通常为显性遗传病）在连续几代的遗传中，发病年龄提前而且病情严重程度增加。例如遗传性小脑性运动共济失调（Marie型) 综合征。,七、遗传早现 (anticipation),七、完全显性(complete dominance)：杂合子可以完全表现出与显性纯合子相同的性状。如短指症，FAP。八、不完全显性(incomplete dominance)：又称中间型显性或半显性，指杂合子的表现介于显性纯合子和隐性纯合子之间。如-地中海贫血和人类对苯硫脲(PTC)的尝味能力。,Complete Dominance,Syndactyly type (MIM 185900 ),Semidominance,Achondroplasia (MIM 100800),九、共显性 (co-dominance)：常染色体上的一对等位基因之间没有显性与隐性的区别，都能在表现型中得到表现。如人 ABO 、MN血型系统。十、不规则显性 (irregular dominance)：杂合子由于某种原因不表现出相应