遗传学课件monogenicdiseasea.ppt

Monogenic Disease,Medical Genetics,TerminologyPedigree symbol&Pedigree analysisPedigree characteristicsTypes of ADInfluential factorEstimate of recurrence risk,Emphasis,Dominant(A)&Recessive(a),Locus&Allele(multiple alleles),Terminology,Homozygote:AA or aa,Heterozygote:Aa,The pedigree is a visual tool for documenting biological relationships in families and the presence of traits or diseases.,1.Pedigree,1.Pedigree,Proband(index case),Proband is the first affected family member who seeks medical attention for a genetic disorder.,1.Pedigree1.1.Pedigree Symbol,III,1 2,1 2 3,1.Pedigree1.1.Pedigree Symbol,Information of family members more than three generationsInformation verified by genetic consultantInvestigating the death cause,death age,consanguineous marriage,fetal death,abortion,neonatal death,1.Pedigree1.2.Pedigree Analysis,AD inheritance are those in which a single copy of a mutant gene on autosome is enough for the trait to be expressed or shown.,2.Autosomal Dominant(AD),The phenotype of the heterozygote(Aa)will be indistinguishable from the phenotype of the homozygous(AA)dominant.,2.Autosomal Dominant(AD)2.1.Complete Dominance,Brachydactyly,type A1(MIM 112500),2.Autosomal Dominant(AD)2.1.Complete Dominance,（引自高波等，2001）,Brachydactyly,type A1(MIM 112500),2.Autosomal Dominant(AD)2.1.Complete Dominance,Pedigree of AD,2.Autosomal Dominant(AD)2.1.Complete Dominance,Pedigree characteristics,Each affected individual has one affected parent50%of sibs and offspring are affectedMales and females are affected with equal probabilityPassed in a vertical fashion,2.Autosomal Dominant(AD)2.1.Complete Dominance,The phenotype of the heterozygote(Aa)will be intermediate between the phenotypes of the two homozygotes(AA or aa).,2.Autosomal Dominant(AD)2.2.Incomplete Dominance,Achondroplasia(MIM 100800),2.Autosomal Dominant(AD)2.2.Incomplete Dominance,（引自Wolf Wikis North Carolina State University）,Achondroplasia(MIM 100800),2.Autosomal Dominant(AD)2.2.Incomplete Dominance,（引自Wolf Wikis North Carolina State University）,Both alleles will be completely expressed in the heterozygote,and the individual has a different phenotype than that of either homozygote.,MN blood group(MIM 111300),ABO blood group(MIM 110300),2.Autosomal Dominant(AD)2.3.Codominance,ABO blood group(MIM 110300),2.Autosomal Dominant(AD)2.3.Codominance,ABO blood group(MIM 110300),2.Autosomal Dominant(AD)2.3.Codominance,FUT1(19q13.33)ABO(9q34),FUT2(19q13.33),Sometime the heterozygote(Aa)will not show the phenotypes of dominant allele,or show different clinical symptoms of it.,2.Autosomal Dominant(AD)2.4.Irregular Dominance,Penetrance,Penetrance in genetics is the proportion of individuals carrying a particular variation of a gene(allele or genotype)that also express an associated trait(phenotype).,2.Autosomal Dominant(AD)2.4.Irregular Dominance,Polydactyly,postaxial,type A1(MIM 174200),2.Autosomal Dominant(AD)2.4.Irregular Dominance,Polydactyly,postaxial,type A1(MIM 174200),2.Autosomal Dominant(AD)2.4.Irregular Dominance,Complete penetranceIncomplete penetrance,Forme frusteSkipped generation,Penetrance,2.Autosomal Dominant(AD)2.4.Irregular Dominance,Expressivity,Expressivity is a term used in genetics to refer to variations in a phenotype among individuals carrying a particular genotype.,2.Autosomal Dominant(AD)2.4.Irregular Dominance,Osteogenesis imperfecta,type(MIM 166200),2.Autosomal Dominant(AD)2.4.Irregular Dominance,2.Autosomal Dominant(AD)2.4.Irregular Dominance,Osteogenesis imperfecta,type(MIM 166200),Marfan syndrome(MIM 154700),2.Autosomal Dominant(AD)2.4.Irregular Dominance,Marfan syndrome(MIM 154700),2.Autosomal Dominant(AD)2.4.Irregular Dominance,Marfan syndrome(MIM 154700),2.Autosomal Dominant(AD)2.4.Irregular Dominance,Marfan syndrome(MIM 154700),2.Autosomal Dominant(AD)2.4.Irregular Dominance,Not all genetic disorders are congenital,some are expressed at a characteristic age and others at variable ages.,2.Autosomal Dominant(AD)2.5.Delayed Dominance,2.Autosomal Dominant(AD)2.5.Delayed Dominance,Huntington disease(MIM 143100),Exon:(CAG)n n=9 34,average 20 n=37100,average 46,Huntingtin(IT 15):4p16.3,Dynamic mutation,Huntington disease(MIM 143100),2.Autosomal Dominant(AD)2.5.Delayed Dominance,Huntington disease(MIM 143100),2.Autosomal Dominant(AD)2.5.Delayed Dominance,AR inheritance are characterized only in individuals homozygous for the mutant gene on autosome.,3.Autosomal Recessive(AR),Carrier(Aa),An individual that carries one gene for a particular recessive trait.A carrier does not express the trait but,when mated with another carrier,can produce offspring that do.,3.Autosomal Recessive(AR),Pedigree of AR,3.Autosomal Recessive(AR),Pedigree of AR,3.Autosomal Recessive(AR),Pedigree characteristics,Both parents are carriers1/4 of sibs are affected.Males and females are affected with equal probability2/3 of unaffected sibs are carriersThe diseases are sporadicThe risk of offspring is higher in consanguineous marriage,3.Autosomal Recessive(AR),AR diseases,Sickle cell disease(MIM 603903),Sickle-cell disease(SCD),or sickle-cell anaemia(SCA),is an AR genetic blood disorder with co-dominance,characterized by red blood cells that assume an abnormal,rigid,sickle shape.,3.Autosomal Recessive(AR),AR diseases,Sickle cell disease(MIM 603903),3.Autosomal Recessive(AR),GAG,GTG,AR diseases,Sickle cell disease(MIM 603903),3.Autosomal Recessive(AR),AR diseases,Sickle cell disease(MIM 603903),3.Autosomal Recessive(AR),AR diseases,Sickle cell disease(MIM 603903),3.Autosomal Recessive(AR),AR diseases,Sickle cell disease(MIM 603903),3.Autosomal Recessive(AR),AR diseases,Phenylketonuria(MIM 261600),Phenylketonuria(PKU)is a rare,inherited,metabolic disorder resulting from a deficiency of phenylalanine hydroxylase(PAH).,3.Autosomal Recessive(AR),AR diseases,Phenylketonuria(MIM 261600),1 in 13333 births,3.Autosomal Recessive(AR),Metabolism of phenylalanine(Phe),Melanin,“Mousy”smell in the sweat and urineLighter colored skin,hair,and eyesMental retardation,3.Autosomal Recessive(AR),AR diseases,Phenylketonuria(MIM 261600),3.Autosomal Recessive(AR),AR diseases,Phenylketonuria(MIM 261600),Guthrie test,24 hours after birth,usually done at age 7 to 10 daysA urine PKU test is done on a baby who is older than 6 weeks,3.Autosomal Recessive(AR),AR diseases,Phenylketonuria(MIM 261600),Guthrie test,3.Autosomal Recessive(AR),AR diseases,Phenylketonuria(MIM 261600),Guthrie test,3.Autosomal Recessive(AR),AR diseases,Phenylketonuria(MIM 261600),Guthrie test,A normal blood phenylalanine level is about 1mg/dlIn cases of PKU,levels may range from 680 mg/dl,but are usually greater than 30 mg/dl,3.Autosomal Recessive(AR),AR diseases,Phenylketonuria(MIM 261600),A strictly controlled phenylalanine free diet up to the age of about 14 years oldPhenylalanine is itself an essential amino acid small doses must be supplied,3.Autosomal Recessive(AR),AR diseases,Phenylketonuria(MIM 261600),The goal of PKU treatment is to maintain the blood levels of pheylalanine between 210 mg/dl,3.Autosomal Recessive(AR),AR diseases,Phenylketonuria(MIM 261600),Women with PKU who wish to become pregnant,Mental retardation 92%Microcephaly 73%Congenital heart defects 12%,3.Autosomal Recessive(AR),AR diseases,Phenylketonuria(MIM 261600),Women with PKU who wish to become pregnant must also eat the special diet.,AR diseases,Albinism,oculocutaneous,type IA,OCA1A(MIM203100)is a genetically heterogeneous congenital disorder caused by mutations in the tyrosinase gene.,3.Autosomal Recessive(AR),AR diseases,Albinism,oculocutaneous,type IA,1 in 20000 10000 births,3.Autosomal Recessive(AR),Tyr,Dopa,Melanin,Tyrosinase,Tyrosinase,3.Autosomal Recessive(AR),AR diseases,Albinism,oculocutaneous,type IA,Characterized by decreased or absent pigmentation in the hair,skin,and eyes.,3.Autosomal Recessive(AR),AR diseases,Albinism,oculocutaneous,type IA,3.Autosomal Recessive(AR),AR diseases,Albinism,oculocutaneous,type IA,3.Autosomal Recessive(AR),AR diseases,Albinism,oculocutaneous,type IA,Two questions,Small familyConsanguineous marriage,3.Autosomal Recessive(AR),Two questions,Small family,Complete ascertainment,Incomplete ascertainmentTruncate ascertainment,3.Autosomal Recessive(AR),Two questions,Small family,A couple of carrier,One child,Two child,3.Autosomal Recessive(AR),Two questions,Consanguineous marriage,Consanguinity,A hereditary or“blood”relationship between persons,because of having a common parent or ancestor.,3.Autosomal Recessive(AR),Coefficient of relationship,Probability that any two individuals share a given gene at a random locus by descended from a common ancestor.,3.Autosomal Recessive(AR),Two questions,Consanguineous marriage,First degree relatives 1/2,Second degree relatives 1/4,Third degree relatives 1/8,3.Autosomal Recessive(AR),Coefficient of relationship,Two questions,Consanguineous marriage,Coefficient of relationship,Two questions,Consanguineous marriage,The gene frequency of AR is 0.01the frequency of carrier is 0.02,The gene frequency of AR is 0.001the frequency of carrier is 0.002,3.Autosomal Recessive(AR),Conclusion,Consanguineous marriage Random marriage,The rarer the AR is,the higher the risk should be,3.Autosomal Recessive(AR),Two questions,Consanguineous marriage,Hemizygote,Hemizygote describes a diploid male who has only one allele on the X-chromosome or one X-chromosome rather than the usual two in a diploid female.,4.X-linked Inheritance,Criss-cross inheritance,A male can only receives an allele on the X-chromosome from his mother and,can only transmits it to his daughter.,Hemizygote,4.X-linked Inheritance,4.X-linked Inheritance4.1.X-linked Dominant(XD),XD inheritance are those in which a single copy of a mutant gene on the X chromosome in a male or female is enough for the trait to be expressed or shown.,Pedigree of XD,4.X-linked Inheritance4.1.X-linked Dominant(XD),Pedigree of XD,4.X-linked Inheritance4.1.X-linked Dominant(XD),Pedigree characteristics,The ratio of affected females to the males is approximately 2 to 1Each affected individual has one affected parentAffected male have no affected sons and no normal daughters;50%offspring of affected female have chance of being affectedPassed in a vertical fashion,4.X-linked Inheritance4.1.X-linked Dominant(XD),Vitamin D resistant rickets(MIM 307800),4.X-linked Inheritance4.1.X-linked Dominant(XD),4.X-linked Inheritance4.2.X-linked Recessive(XR),XR inheritance are characterized only in female homozygous for the mutant gene on the X chromosome.,4.X-linked Inheritance4.2.X-linked Recessive(XR),Pedigree of XR,4.X-linked Inheritance4.2.X-linked Recessive(XR),Pedigree of XR,4.X-linked Inheritance4.2.X-linked Recessive(XR),Pedigree of XR,Pedigree characteristics,More affected males than affected femalesEach son has 1/2 chance of being affectedBecause of criss-cross inheritance,who(?)of affected individual have chance of being affectedPassed with female carriers,4.X-linked Inheritance4.2.X-linked Recessive(XR),Muscular dystrophy,Duchenne(DMD)MIM 310200,4.X-linked Inheritance4.2.X-linked Recessive(XR),Gower sign,Muscular dystrophy,Duchenne(DMD)MIM 310200,Becker(BMD)MIM 300376,4.X-linked Inheritance4.2.X-linked Recessive(XR),Hemophilia A(MIM 306700),Chromosome:Xq28 Gene:Fc,4.X-linked Inheritance4.2.X-linked Recessive(XR),Hemophilia A:“the Royal Disease”,Red-green colorblindness,Opsin genes,4.X-linked Inheritance4.2.X-linked Recessive(XR),Red-green Colorblindness,（引自Google images）,Red-green Colorblindness,Red-green Colorblindness,（引自JOSHUA KENNON,2012）,Red-green Colorblindness,Holandric inheritance,Inheritance of genes on the Y chromosome.Since only males have a Y chromosome,Y-linked genes can only be transmitted from father to son.,5.Y-linked Inheritance,Hairy Ears(MIM 425500),Holandric inheritance,5.Y-linked Inheritance,A similar phenotype being caused by different hereditary basis.,Allelic heterogeneity,Locus heterogeneity,6.Influencing Factor6.1.Genetic Heterogeneity,Locus heterogeneity,A similar phenotype being caused by different genes.,6.Influencing Factor6.1.Genetic Heterogeneity,Deafness,Autosomal dominant,Autosomal recessiveX-linked recessiveMitochondrial,Locus heterogeneity,6.Influencing Factor6.1.Genetic Heterogeneity,Locus heterogeneity,Deafness,AR(MIM 220700),1 in 1000 individuals worldwide 68%of congenital deafness is ARHomozygosity at any one of 35 loci 16%of population are carriers,6.Influencing Factor6.1.Genetic Heterogeneity,Locus heterogeneity,Deafness,AR(MIM 220700),6.Influencing Factor6.1.Genetic Heterogeneity,Double heterozygote,Locus heterogeneity,Deafness,AR(MIM 220700),6.Influencing Factor6.1.Genetic Heterogeneity,Pleiotropy describes the genetic effect of a single gene on multiple phenotypic traits.,6.Influencing Factor6.2.Pleiotropy,Secondary effect,Primary effect,The genetic phenomenon involved in the control of a small proportion of genes in the genome,where the allele that is expressed is determined solely on which parent contributes it.,6.Influencing Factor6.3.Genetic Imprinting,The genetic disorders are autosomally transmitted but expressed in only one sex.,6.Influencing Factor6.4.Sex-limited Inheritance,A autosomal dominant expression that depends on the sex of the individual.,6.Influencing Factor6.5.Sex-influenced Inheritance,Baldness(MIM 109200),6.Influencing Factor6.5.Sex-influenced Inheritance,An environmentally induced,non-hereditary variation in an organism,closely resembling a genetically determined trait.,6.Influencing Factor6.6.Phenocopy,Deafness,aminoglycoside-induced,Deafness,AR(MIM 220700),7.Estimate of Recurrence Risk,The study of an inherited trait in a group of related individuals to determine the pattern and characteristics of the trait,including its mode of inheritance,recurrence risk,et al.,7.Estimate of Recurrence Risk7.1.Pedigree Analysis,7.Estimate of Recurrence Risk7.2.Coefficient of Relationship,7.Estimate of Recurrence Risk7.2.Coefficient of Relationship,7.Estimate of Recurrence Risk7.2.Coefficient of Relationship,7.Estimate of Recurrence Risk7.2.Coefficient of Relationship,7.Estimate of Recurrence Risk7.2.Coefficient of Relationship,ConceptPedigree symbol&Pedigree analysisPedigree characteristicsTypes of ADInfluential factorEstimate of recurrence risk,Emphasis,