医学遗传学英文版课件合辑（共477页）

医学遗传学英文版课件合辑（共医学遗传学英文版课件合辑（共477页）页）目录目录1.1.Monogenic disorderMonogenic disorder2.Complex Dis2.Complex Dis3.genetic diagnosis 13.genetic diagnosis 14.genetic diagnosis 24.genetic diagnosis 25.Genetic Variation in Population5.Genetic Variation in Population6.Inborn error of metabolism and molecular disease6.Inborn error of metabolism and molecular disease7.mt7.mt8.8. Nussbaum RL, et al. 张咸宁张咸宁,等等. Thompson & Thompson Genetics in Medicine, 7th ed. （双语版）北京大学医学出版社（双语版）北京大学医学出版社, 2009. Suggested Readings Turnpenny P, Ellard S. Emerys elements of medical genetics: With Student Consult Access. 14th edition. Churchill Livingstone, 2012 Jorde LB, et al. Medical genetics. 4th ed. Mosby, 2010. Passarge E. Color atlas of genetics. 4th ed. Thieme Medical Publishers, 2013 Scriver CR, et al. The metabolic and molecular bases of inherited disease.8th ed. McGraw-Hill Companies, 2001 Rimoin DL , et al. Emery and Rimoins Principles and Practice of Medical Genetics. 5th ed. Churchill Livingstone, 2006 Tobias ES, et al. Essential Medical Genetics. 6th ed. Wiley-Blackwell, 2011 Schaaf CP, et al. Human Genetics: From Molecule to Medicine. LWW, 2012 Young ID. Medical Genetics. OUP, 2010 Strachan T, Read A. Human molecular genetics. 4th ed. Garland Science, 2010 CNS NEJM Lancet Nature Medicine Nature Genetics AJHG AJMG Nat. Rev. Genet. Annu. Rev. Genomics Hum. Genet. Annu. Rev. Genet. Trends Mol Med Genome Res. Hum. Mol. Genet. Hum. Mutat. J. Med. Genet. Genetics in MedicineUseful Internet Information on any mendelian phenotype: www.omim.org Genome data: www.ensembl.org; http:/genome.cse.ucsc.edu Information on proteins: http:/ca.expasy.org Biomedical literature: www.ncbi.nlm.nih.gov/entrez/ Human gene mutation database: www.hgmd.org Human disease genes list: http:/bioinfo.weizmann.ac.il/cards Genetic diagnosis: www.genetests.org 1966:MIM（McKusick VA, 1921-2008）http:/www.omim.org Last updated:7/31/2014. Numbers of reference: 88. Pubmed search references: 93564 !Monogenic disorder(Patterns of single-gene disorder)ZHANG Xian-Ning, PhD Tel：13105819271; 88208367 Office: C303, Teaching Building2014/09Genotype: The combination of alleles that an individual possesses.Phenotype: The physical characteristics of a cell or organism as defined by its genetic constitution.Monogenic disorder Allele: One of the variant forms of a gene at a particular locus, or location, on a cs. Different alleles produce variation in inherited characteristics such as hair color or blood type. Pedigree: A simplified diagram of a familys genealogy that shows family members relationships to each other and how a particular trait or disease has been inherited. Proband: The family member who first bring a family to the attention of an investigator is proband. Pedigree symbolsProband（先证者）（先证者）: III-5Pedigree drawing software：Progeny, etc.Major Patterns of Monogenic Inheritance Patterns of autosomal dominant inheritance (AD) Patterns of autosomal recessive inheritance (AR) Patterns of X-linked dominant inheritance (XD) Patterns of X-linked recessive inheritance (XR) Patterns of Y-linked inheritance Autosomal DominantADADADAD requires mutation in only one allele to produce disease males and females equally affected family history usually positive, with affected members in each generation may show apparent generation skipping due to variable penetrance, variable expressivity, or appearance of a new mutation in the family Examples: Huntington disease, Marfan syndrome, neurofibromatosis, familial breast/ovarian cancer, myotonic dystrophyADHuntington Disease (HD) A progressive disorder of motor, cognitive, and psychiatric disturbances. The mean age of onset is 35 to 44 years and the median survival time is 15 to 18 years after onset. inherited in an AD manner. Offspring of an individual with a mutant allele have a 50% chance of inheriting the disease-causing allele. HD case-Woody Guthrie(1912-1967)Huntington Disease (HD) Frequency estimated to be about 3-7/100 000 in populations of western European descent. AD, Homozygotes for HD appear to have a similar age of onset to heterozygotes, but may exhibit an accelerated rate of disease progression. The HD gene is the only gene associated with Huntington disease. A trinucleotide CAG repeat expansion in Exon 1 is the only mutation observed. Anticipation:Trinucleotide CAG repeat sizes in HD Normal 26 Mutable 27-35 Reduced penetrance 36-39 Fully penetrance 40Anticipation the phenomenon in which increasing disease severity or decreasing age of onset is observed in successive generations, is known to occur in HD. occurs more commonly in paternal transmission of the mutated allele. The phenomenon of anticipation arises from instability of the CAG repeat during spermatogenesis. Large expansions (i.e., an increase in allele size 27 CAG repeats) occur almost exclusively through paternal transmission. Most often children with juvenile-onset disease have inherited the expanded allele from their fathers. 4p16.3, mapped in 1983. HD gene, isolated in 1993 using haplotype analysis of linkage disequilibrium. Huntingtin, a protein of 3144 amino acids with a predicted molecular mass of 348 kd. The CAG repeat in the HD gene is translated into an uninterrupted stretch of glutamine residues that when expanded may have altered structural and biochemical properties. Huntington Disease (HD)Mary (35 y.o.), Samuel (30 y.o.), and Alice (29 y.o.) are siblings at 50% risk to inherit Huntington disease from their father, John, who was found to have a mutable normal allele when he was tested following diagnosis of his brother, Bart. All three siblings chose molecular genetic testing following genetic counseling and neurologic evaluation. All have normal neurologic examinations.Mary38 CAG repeatsSamuel35 CAG repeatsAlice42 CAG repeatsBartJohnMutable normalMolecular Genetic TestingDiagnosisSamuel (35 repeats) is told that he has a mutable normal allele. Expansions of 27-35 CAG repeats have never been associated with clinical symptoms of HD; however, his children are at some risk to inherit an allele with a larger allele size which could result in symptomatic HD. MarySamuel (30 y.o.)35 CAG repeatsMutable normal alleleAliceMary (38 repeats) is told that she has a reduced penetrance allele. Expansions of 36-40 CAG repeats may or may not cause symptoms of HD during a normal life span. The onset of symptoms may be later than typically observed. Marys children are at 50% risk for inheriting the abnormal allele, which could remain in the reduced penetrance range or expand into the full penetrance range. Mary (35 y.o.)38 CAG repeatsReduced penetrance alleleSamuelAliceAlice (42 repeats) is told that she has a full penetrance allele. Expansions of 41 CAG repeats or greater are always associated with symptomatic HD if the individual lives a normal life span. Alices children are at 50% risk to inherit the full penetrance allele and therefore to develop HD.MarySamuelAlice (29 y.o.)42 CAG repeatsFull penetrance alleleHD gene-Hero! In 1983, HD was the first genetic disease to be localized to a chromosome location (4p16.3) with RFLP linkage analysis. (Gusella et al.) Robertson:“The beginning of the end of dilemma?” (Nature) The HD gene, Huntingtin, was isolated in 1993 after a decade of intense collaborative efforts among many laboratories from various countries and officially designated HD. (Gusella et al.) Little:“Huntingtons disease: The end of the beginning” (Nature)Locations of RepeatsRichards & Sutherland, TIBS, 1997, 22:432.Fragile X Syndrome Macrocephaly Large ear with soft cartilage Normal life span CGG trinucleotide repeatMarfan Syndrome is a Group of Features These features include: OcularLens dislocationabout 70% by age 6-10 years CardiovascularAortic dilatationabout 50% by age 10Aortic dissectionabout 50% by age 48Mitral valve prolapseabout 75% by age 12 MusculoskeletalHeight/span and US/LS 75% by age 12 yearsPectus excavatum (“hollow chest”), 75% by age 15 years Dural ectasia?100% by age 20 years Family history60%-75% by age 10 yearsMarfan Syndrome: An example of Pleiotropy Frequency estimated to be about 1/15 000 AD inheritance but about 25% represent new mutation Mutations in the FBN1 gene (15q21.1) cause MSThese mutations (200) affect Protein folding Intracellular transport Secretion Formation of extracellular microfibrilsMS-Hyman(1954-1986) ,朱刚朱刚(1971-2001), 武武强强(1986-2009), 张佳迪张佳迪(1988-2012) bone fragility reduced life span short stature dentinogenesis hearing loss affects 1/10 000 individualsOI type I Blue sclerae Near normal height Fractures Hearing loss Dominant inheritanceOI type II Severe bone compression Soft calvarium Blue sclerae Perinatal death New in familyOI type III Very short Marked and progressivedeformity Blue or normal sclerae Dentinogenesis imperfecta Often non-ambulatory Often new in familyOI type IV Normal sclerae Mild-moderate short stature Fractures Dentinogenesis imperfecta Bone deformity Dominant inheritance AD null or structural mutations in type I collagen a chain genes lead to different types of OI dominant negative effect haploinsufficiency germline mosaicismClassic Ehlers-Danlos syndrome(EDS) More than 70% have mutations in COL5A1 (9q34.2-q34.3) of which a third have premature termination codons Rare mutations in COL5A2 (2q31) Even rarer in COL1A1 (17q21.3-q22) 50% have a de novo mutationEric was 9 years old when he presented to Medical Genetics Clinic for chronic joint dislocation and child abuse. His past medical history was significant for child abuse, for which he was removed from his home on several occasions. On examination he had marked scarring of his forehead, chin, and knees. He had hemosiderin deposition on his shins with thin atrophic shiny skin. His joints were lax and he had pes planus with weight bearing and genu recurvatum. He could stick out his tongue and touch his nose.A diagnosis of Ehlers-Danlos type I was made and he was returned to his home,where he once again suffered abuse at the hands of his mother and her boy friend.EDS type I4.5-year-old boyUnusual Features of Autosomal Dominant Inheritance1. Reduced penetrance2. Variable expressivity3. High frequency of new mutationsAutosomal Recessive(AR)ARARAR requires mutation of both alleles to produce disease males and females equally affected higher frequency in consanguineous matings higher frequency of mutation carriers in particular ethnic groups family history often negative often associated with enzymatic defects causing metabolic disorders Examples: sickle cell disease, phenylketonuria, cystic fibrosis, spinal muscular atrophy, Wilson disease AR Develop in persons who receive two copies of the mutant gene, one from each parent who is a carrier. Carrier: a person who has a recessive mutated gene, together with its normal allele. Carriers do not usually develop disease but can pass the mutated gene on to their children.Sickle cell anemia lethal disease in which a defect (Glu6Val) in 146 AA -hemoglobin, the oxygen-carrying pigment in the blood, causes Hb aggregation and distortion (sickling) and loss of red blood cells, producing damage to organs throughout the body 1st identified Hb disease 1/600 African Americans HbS -CCT GTG GAG-Pro Val Glu-HbA -CCT GAG GAG-Pro Glu Glu-6 6Cystic Fibrosis ( CF ) Severe progressive disease of the bronchial system and gastrointestinal tract Disturbed function of a chloride ion channel by mutations of one gene, CFTR (Cystic fibrosis transmembrane conduction regulator) on 7q31.3, 24 exons, 6.5-kb transcript, 1480 amino acids. AR Disease incidence approx. 1:2000 in Caucasian. CFTR Gene 1st gene identified by positional cloning Identified by the research group led by Dr. Lap-Chee Tsui (徐徐立之立之) at Toronto, Canada- (1989) Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245: 1059-1065. - (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245: 1066-1073. - (1989) Identification of the cystic fibrosis gene: genetic analysis. Science 245: 1073-1080. CFOther Examples of Phenylketonuria ( PKU ): Gene locus (PAH) : 12q22-24. Disease incidence 1:16000, cirrhosis of liver, galactosuria and mental retardation. Mutations in the gene for phenylalanine hydroxylase. Albinism: A pigmentless “white” phenotype, determined by a mutation in a gene coding for a pigment-synthesizing enzyme. Spinal muscular atrophy (SMA) A disorder characterized by degeneration of lower motor neurons and occasionally bulbar motor neurons leading to progressive limb and trunk paralysis as well as muscular atrophy. It is a clinically and genetically heterogeneous group of neuromuscular diseases. It is the second most common lethal autosomal recessive disorder after cystic fibrosis in Caucasian populations with an overall incidence of 1 in 10000 live births and a carrier frequency of approximately 1 in 50.Spinal muscular atrophy (SMA)Wilson disease: Cu toxicity, ARWilson SAK. Brain, 1912; 34:295-507 Wilson disease:Before/After penicillamine therapyX-linked Recessive (XR)XRXRXRXR due to a recessive mutation located on the X-chromosome males predominantly or exclusively affected mothers are carriers no male-to-male transmission some cases due to appearance of a new mutation in the family Examples: Duchenne muscular dystrophy(DMD), color blindness, hemophilia A, glucose-6-phosphate dehydrogenase (G6PD) deficiencyXRXR Hemizygote: no corresponding loci on the Y chromosome, only one allele of each X chromosome locus. XRDuchenne Muscular Dystrophy (DMD)(Also known as Pseudohypertrophic) Definition One of nine types of muscular dystrophy, a group of genetic, degenerative diseases primarily affecting voluntary muscles. Cause An absence of dystrophin, a protein that helps keep muscle cells intact. Onset Early childhood - about 2 to 6 years. Symptoms Generalized weakness and muscle wasting first affecting the musclesof the hips, pelvic area, thighs and shoulders. Calves are often enlarged. Progression DMD eventually affects all voluntary muscles, and the heart and breathing muscles. Survival is rare beyond the early 30s. A less severe variant is Becker muscular dystrophy. Inheritance XR. DMD primarily affects boys (1/3500 world-wide), who inherit the disease through their mothers. Women can be carriers of DMD but usually exhibit no symptoms.DMDDMD: Gowers maneuver Genetics of DMD occurring in about 1 in 3500 males, onset in early childhood, death by 3rd decade male births; X-linked recessive, lethal in males 1/3 of patients are new mutants; 2/3 have carrier mothers dystrophin, Xp21, Extremely large gene (more than 2000 kb), 79 exons. High mutation rate, probably due to large size of gene, 60% to 65% of the mutations are deletions, and about 6% are duplications , Allelic mutations in the same gene cause a milder disorder, Becker muscular dystrophy. DMD (OMIM 310200): Xp21.2, 79 Exons, 2.4 mbOther Examples of XR Hemophilia A: a classical example anti Hemophilia factor deficiency. Glucose-6-Phosphate dehydrogenase deficiency (G6PD): G6PD is in the hexose monophosphate pathway, the only NADPH-generation process in mature red cells, which lack the citric acid cycle. For this reason G6PD deficiency has adverse physiologic effects. Deficiency of the red cell enzyme, in various forms, is the basis of favism, primaquine sensitivity and some other drug-sensitive hemolytic anemias, anemia and jaundice in the newborn, and chronic nonspherocytic hemolytic anemia Red- green color blindness: Color blindness afflicts 8% of males and 0.04 % of human females. X-linked dominant(XD)XDXD due to a dominant mutation located on the X-chromosome males and females usually equally affected no male-to-male transmission; all daughters of an affected father are affected Examples: hypophosphatemic rickets, incontinentia pigmentiXDExamples of XD Disorders Vitamin D-resistant rickets: There were no instances of male-to-male transmission of either bone disease or hypophosphatemia, and all daughters of hypophosphatemic males were themselves hypophosphatemic. Affected persons show a reduction in renal phosphate Tm to about 50% of normal. Males and females are not significantly different in this respect. caused by mutation in the phosphate-regulating endopeptidase gene (PHEX).Vitamin D-resistant rickets:Xp22.2-p22.1Y-linked Haired earsY-linked Disorders they are always passed from father to son, and they never appear in females SRY(sex-determining region Y) : Analysis of such individuals has revealed some of the molecules involved in sex determination, including one called SRY, which is important for testis formation. The testis-determining factor (TDF), formed under the influence of the SRY gene, induces the development of the fetal testis from an undifferentiated gonad. Factors affecting pedigree patterns Onset age Pleiotropy: multiple effects of a single gene (one gene, more than one effect )Genetic heterogeneity Expressivity and penetranceCoefficient of relationship and consanguineous marriage Sex-limited phenotypes and sex-influenced phenotypesgenomic imprinting Anticipation X inactivation, Pleiotropy multiple effects of a single gene (one gene, more than one effect ) E.g.: Marfan syndrome (FBN1 gene) Genetic Heterogeneity The phenomenon that a disorder can be caused by different allelic or non-allelic mutations. Locus heterogeneity Allelic heterogeneity Phenotypic (Clinical) heterogeneityGenetic Heterogeneity Allelic heterogeneity: In a population, there may be a number of different mutant alleles at a single locus. In an individual, the same or similar phenotypes may be caused by different mutant alleles rather than by identical alleles at the locus. E.g.: nearly 1400 different mutations have been found worldwide in the CFTR among patients with cystic fibrosis (CF). Genetic Heterogeneity Locus heterogeneity: The production of identical phenotypes by mutations at two or more different loci. E.g.: Osteogenesis Imperfecta (OI) or Brittle bone disease: Cs 7 & 17.Genetic Heterogeneity Phenotypic (Clinical) heterogeneity: The term describing the occurrence of clinically different phenotypes from mutations in the same gene. E.g.: RET gene mutation caused Hirschsprung disease or multiple endocrine neoplasia type 2A and 2B or both.Expressivity and Penetrance Expressivity: Variation in the severity of the phenotypic features of a particular gene. Penetrance: The proportion of heterozygotes for a dominant gene who express a trait, even if mildly.Sex-limited phenotypes and Sex-influenced phenotypes Sex-limitation: When a trait is only manifest in individuals of one sex. Sex-influence: When a genetic trait is expressed more frequently in one sex than another.Genomic imprinting The phenomenon of a gene or region of a chromosome showing different expression depending on the parent of origin.Anticipation The tendency for some AD diseases to manifest at an earlier age and/or to increase in severity with each succeeding generation.49,XXXXYX inactivation (lyonization) Inactivation of genes on one X chromosome in somatic cells of female mammals, occurring early in embryonic life, at about the time of implantation. A random and permanent event.Mechanisms of Epigenetic Inheritance Epigenetic: The term that refers to any factor that can affect gene function without change in the genotype. DNA methylation Genomic imprinting (parent-of-origin silencing) Histone Modifications Regulatory non-coding RNAs Short interfering RNA (siRNA) Micro RNA (mirRNA) Double-stranded RNA (dsRNA) Short heterochromatic RNA (shRNA) Transcripts from repeated sequences (Alu, LTR) Ribosomal and transfer RNAsTypes of non-protein coding RNAsZHANG Xian-Ning, PhD Tel：13105819271; 88208367 Office: C303, Teaching Building2014/10Any disease is the result of the combined action of genes and environment Classification of genetic disorders:1. Chromosome disorders:2. Single-gene disorders:3. Complex (multifactorial, polygenic) disorders:4. Somatic cell genetic disorders:5. Mitochondrial gen