1、 ng.htm#國際罕見病日 Classification of genetic disorders Single-gene disorders(單基因?。﹩位虿。?Polygenic disorders（多基因?。ǘ嗷虿。?Chromosomal disorders（染色體病）（染色體?。?Genetic diseases of mitochondria (Mt) （線粒體遺傳病）（線粒體遺傳?。?Somatic cell Genetic disorders（體細(xì)胞（體細(xì)胞遺傳?。┻z傳病）Brief reminderBrief reminder Autosomes Chromosome

2、s 1-22 An individual inherits one chromosome from each parent An individual therefore inherits a paternal copy and a maternal copy of an autosomal gene Sex chromosomes X and Y A female inherits an X from their mother and an X from their father A male inherits an X from their mother and the Y from th

3、eir father Single gene disorders Number of Entries in OMIM (Updated 19 February 2014) : PrefixAutosomal X LinkedY Linked MitochondrialTotals* Gene description 13,737670483514,490+ Gene and phenotype, combined100202104# Phenotype description, molecular basis known3,7272824284,041% Phenotype descripti

4、on or locus, molecular basis unknown1,577135501,717 Other, mainly phenotypes with suspected mendelian basis1,745116201,863 Totals20,8861,205596522,215Number of Entries in Online Mendelian Inheritance in Man (OMIM )(Updated 4 March 2013) : PrefixAutosomal X LinkedY LinkedMitochondrialTotals* Gene des

5、cription13,441655483514,179+ Gene and phenotype, combined124402130# Phenotype description, molecular basis known3,4262724283,730% Phenotype description or locus, molecular basis unknown1,625133501,763 Other, mainly phenotypes with suspected mendelian basis1,758124201,884 Totals20,3741,188596521,686

6、Conception locus(基因座基因座): Particular chromosomal location alleles (等位基因等位基因) : alternative variants of genetics information at a particular locus genotype (基因型基因型) : the set of alleles that make up genetic constitution of a person, either collectively at all loci or, more typically, at a single locu

7、s phenotype(表型表型): the observable expression of a genotype as a morphological, clinical, biochemical, or molecular trait homozygote(純合子純合子) & heterozygote(雜合子雜合子): a person who has a pair of identical alleles; a person who has a pair of different alleles dominant (顯性顯性) & recessive(隱性隱性) :a

8、phenotype expressed in the same way in both homozygotes and heterozygotes is dominant; a phenotype only in both homozygotes is recessive Outline Pedigree and pedigree analysis Autosomal Dominant Inheritance Autosomal Recessive Inheritance X-linked Dominant Inheritance X-linked Recessive Inheritance

9、Y-linked inheritance Factors that may complicate inheritance patterns of single-gene disorders Pedigree (系譜) In medical genetics, a family history of a hereditary condition, or a diagram of a family history indicating the family members, their relationship to the proband, and their status with respe

10、ct to a particular hereditary condition. pedigree analysis(系譜分析) proband(先證者)或index case(索引病例) The member through whom a family with a genetic disorder is first brought to attentionRelationship within a kindred (page 112 in the textbook) Autosomal dominance inheritance (AD)Gene : A (mutant allele),

11、aGenotype : AA, Aa, aaAaaaP1 : 1F1G Autosomal dominance inheritance (AD)Pedigree showing typical inheritance of a form of progressive sensorineural deafness (DFNA1) inherited as an autosomal dominant trait Characteristics of Autosomal Dominant inheritance 1. The phenotype usually appears in every ge

12、neration, each affected person having an affected parent Exceptions : (1)fresh mutation (2)the disorder is not expressed or is expressed only subtly in a person who has inherited the responsible gene. 2. Any child of an affected parent has a 50 percent risk of inheriting the trait 3. both males and

13、females are affected in a 1 : 1 ratio Syndactyly type 并指并指型型 (MIM 185900 ) 1 2 1 2 3 1Achondroplasia軟骨發(fā)育不全軟骨發(fā)育不全(MIM 100800)Achondroplasia, ACH heterozygoteIn virtually every reported examples, homozygosity for a defective allele that causes an autosomal dominant disease results in a more severely a

14、bnormal phenotype than does heterozygosity for that allele. (incomplete dominant or semidominant)Familial hypercholesterolemia (FH) 家族性高膽固醇血癥家族性高膽固醇血癥FH homozygote FH heterozygotePolydactyly postaxial 多指軸后多指軸后型型 (MIM 174200)Polydactyly postaxial 多指軸后多指軸后型型 (MIM 174200)blood typered cell antigens ant

15、ibodygenotypeA AA AIAIA, IAiIAIA, IAiB BB BIBIB, IBiIBIB, IBiABABABABIAIBIAIBO O, iiiiABO blood typeABO blood typePF1G Autosomal Recessive Inheritance (AR) Characteristics of Autosomal Recessive Inheritance 1. An autosomal Recessive phenotype, typically is seen only in the sibship of the proband, no

16、t in parents, offspring, or other relatives. 2. both sexes are affected with equal frequency at a ratio of 1:1 3. Parents of an affected child are asymptomatic carriers of mutant alleles. heterozygous parents have a risk of 25% of affected offspring 4. The parents of the affected person may in some

17、cases be consanguineous. This is especially likely if the mutant gene is rare in the population. 苯丙酮尿癥（苯丙酮尿癥（phenylketonuria）,我國的發(fā)生率為我國的發(fā)生率為1/16500由于缺乏苯丙氨酸羥化酶不能生成酪氨酸，大量苯丙氨酸脫氨后生由于缺乏苯丙氨酸羥化酶不能生成酪氨酸，大量苯丙氨酸脫氨后生成苯丙酮酸，導(dǎo)致苯丙氨酸及其酮酸蓄積并從尿中大量排出。成苯丙酮酸，導(dǎo)致苯丙氨酸及其酮酸蓄積并從尿中大量排出。主要臨床特征為智力低下、精神神經(jīng)癥狀、濕疹、皮膚抓痕征及色主要臨床特征為智力低下、

18、精神神經(jīng)癥狀、濕疹、皮膚抓痕征及色素脫失和鼠尿氣味、腦電圖異常素脫失和鼠尿氣味、腦電圖異常 Criss-cross inheritance (交叉遺傳交叉遺傳) Male (XY) Male (XY) Female (XX) Son (XY) Daughter (XX)1:1P1:1:1:1F1G X-linked Dominant Inheritance (XD) Characteristics of X-linked Dominant Inheritance 1. The incidence of the trait is much higher in females than in ma

19、les (about twice) ,but affected females typically have milder (variable) expression of the phenotype. 2. Affected males with normal mates have normal sons and Affected daughters. 3. Both male and female offspring of Affected female have a 50 percent risk of inheriting the phenotype. 4.The pedigree p

20、attern is the same as autosomal dominant inheritance. Vitamin D resistant rickets抗維生素抗維生素D佝僂病佝僂病(MIM 307800)Male lethality may complicate X-linked pedigreesFor some X-linked dominant conditions, absence of the normal allele is lethal before birth. Thus affected males are not born, and we see a condi

21、tion that affects only females, who pass it on to half their daughters but none of their sons X-linked dominant incontinentia pigmenti (OMIM#308300). Affected males abort spontaneously (small squares). Female XA XA , XA Xa , Xa Xa Male XAY , XaYGenotype:1 : 1P1 : 1 : 1 : 1F11 : 1 : 1 : 1 X-linked Re

22、cessive Inheritance (XR) Characteristics of X-Linked Recessive InheritanceThe incidence of the trait is much higher in males than in females. The gene is ordinarily never transmitted directly from father to son (male-to-male), but it is transmitted by an affected male to all his daughters . A carrie

23、r Female for an X-chromosomal mutation has a risk of 50% For an affected son. The gene may be transmitted through a series of carrier females; affected males inherit the mutant allele from the mother only Heterozygous females are usually unaffected, but some may express the condition with variable s

24、everity as determined by the pattern of X inactivationLyon hypothesisThe Lyon hypothesis of random X chromosome inactivation in female somatic cells. Immunostaining for dystrophin In muscle specimenA normal femaleA male with DMDA carrier femaleDystrophin gene Mutations:Dystrophin gene Mutations: del

25、etions 2/3 (first 20 exons or exons 45-53) deletions 2/3 (first 20 exons or exons 45-53) duplication duplication Muscular dystrophy,MD(肌營養(yǎng)不良肌營養(yǎng)不良)IrelandGermanyRussianSpainHemophilia B(MIM 306900)Royal Disease Genotype analysis identifies the cause of the Royal disease. Science 326: 817, 2009 Y-link

26、ed inheritance hairy ears 多毛耳多毛耳(MIM 425500) Common recessive conditions can mimic a dominant pedigree pattern(常見的隱性遺傳常見的隱性遺傳表型可模擬常染色體顯性系譜模式表型可模擬常染色體顯性系譜模式)Aa?Fragile bonesDeafnessSoft teethBlue scleraeVariable expressivity: heterozygotes have different phenotypesSecondary effect (次級效應(yīng))Multiple phenotypic effects of a single gene or gene pair.Galactosemia 半乳糖血癥半乳糖血癥 (MIM 230400) male-limited Precocious pubertyResults by instable (triplet repeat) mutationCommon recessive conditions can mimic a dominant pedigree