3、Single gene disorder.doc

Single-gene disorders1、TerminologyAllele：is alternative variations of genetic information at a particular locus on a choromosome. Genotype: is the set of alleles that make up a persons genetic constitution at a single locus. Phenotype:is the observable expression of a genotype as a morphological, clinical or molecular trait. Homozygous:when a person has a pair of identical alleles in a locus,he is said to be homozygous.Heterozygous:when the alleles are different ,he is said to be heterozygous.Dominant:with a dominant genetic disorder ,one abnormal copy of the gene will cause the disease.Recessive:both copies of the gene must be abnormal in order for a person to be affected by the Disease.Pedigree:is a family tree which made up by symbols and lines,represent a patients genetic family History.Pedigree analysis: （1） Information of family members more than three generations家系越大越好，患者与正常人的信息都采（2）Information verified by genetic consultant（3）Investigating the death cause, death age, consanguineous marriage, fetal death, abortion, neonatal death（4） Determine the mode of inheritance:遗传方式 dominant, recessive, partial dominance, sex-linked, autosomal, mitochondrial, maternal effect.母体效应（5）Determine the probability of an affected offspring for a given cross.2、Patterns of single gene disorders （1）Factors determined the classification Chromosome location Dominant or recessive （2）Basic patterns of single gene disorders Dominant RecessiveAutosomal Autosomal dominant (AD) Autosomal recessive (AR)X-linked X-linked dominant (XD) X-linked recessive (XR)Y-linked Y-linked3、Autosomal Recessive (AR)l Definition：AR are presented only in individuals who are homozygous for the mutant gene on autosome.l Carrier (Aa )：An individual who carries one gene for a particular recessive trait. A carrier does not express the trait, while they could have an affected offspring when mating with another carrier.l Pedigree Characteristics of AR（1）Affects both sexes equally（2）A child of unaffected carrier parents has 25% risk of disease（3）Few affecters, usually only in one generation（4）Increased risk in consanguineous mating l Coefficient of relationship亲缘系数The probability that any two individuals share a given gene at a random locus from a common ancestor.l Consanguineous mating 近亲婚配Consanguineous mating could increase the risk of affected. More rarer the autosome recessive is, more higher the risk inceresed. l Disease: PKU, Albinism 4、 Autosomal Dominant (AD)Definition: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.Subtypes of AD:（1） Complete dominance Brachydactyly短指症The phenotype of the heterozygote (Aa ) will be indistinguishable from the phenotype of the homozygous (AA ) dominant.杂合子患者和纯合子患者表型没有区别Pedigree Characteristics：v Each affected individual has one affected parent. Passed in a vertical fashion垂直传递v 50% of offspring are affected v 50% of sibs同胞 are affected. v Males and females are affected with equal probability（2） Incomplete dominance (semi-dominance) Achondroplasia软骨发育不全 (MIM 100800)The phenotype of the heterozygote (Aa) will be intermediate between the phenotypes of the two homozygotes (AA or aa ). （3） Codominance共显性 ABO blood groupBoth alleles will be completely expressed in the heterozygote, and the individual has a different phenotype with either of the homozygote. （4） Irregular dominance Polydactyly, postaxialSometime the heterozygote (Aa ) will not show the phenotypes of dominant allele, and sometimes they will show different clinical symptoms. Penetrance外显率：is defined as the percentage of individuals with a given genotype who exhibit the phenotype associated with that genotype. The individuals without the phenotypes were called forme fruste.顿挫型 Irregular dominance Forme fruste Skipped generationExpressivity表现度 ：Expressivity is the severity of expression of the phenotype among individuals with the same disease-causing genotype. 基因型相同有不同的表型Individuals with the same principal gene shows different phenotypes.（5） Delayed dominance延迟显性 Huntington diseaseNot all genetic disorders are congenital先天的, some are expressed at a characteristic age and others at variable ages. 动态突变5、X-linked InheritanceX-linked diseases are single gene disorders that reflect the presence of defective错误的 genes on the X chromosome. Hemizygous半合子：describes a diploid male who has only one allele on the X-chromosome rather than the usual two in a diploid female.Criss-cross inheritance交叉遗传：Male can only receive alleles on the X-chromosome from his mother and transmits it to his daughter.X-linked recessive inheritance (XR)：a recessive faulty有缺陷的 gene that is located on the X Chromosome Eg: Hemophilia A血友病, Red-green colorblindnessPedigree Characteristics of XR（1）Affects almost exclusively专门地 men（2）Affected men born from carrier mother, with 50% risk to be affected（3）No male to male transmission女性症状较男性轻是由于Lyonization6.X-linked dominant inheritance (XD):X-linked dominant inheritance is a gene responsible for a genetic disorder is located on the X chromosome, and only one copy of the allele is sufficient to cause the disorder when inherited from a parent who has the disorder. Eg:Vitamin D Resistant RicketsPedigree Characteristics of XD（1）More females affected than males, the ratio is approximately 2 to 1（2）All daughters of affected males are affected, all sons of affected males are normal（3）A child of an affected female has 50% risk to be affected纯合子的概率