1、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 disorder 2.Complex Dis2.Complex Dis 3.genetic diagnosis 13.genetic diagnosis 1 4.genetic diagnosis 24.genetic diagnosis 2 5.Genetic Variation in Population5.Genetic Variation in Population 6.Inborn error of metabolism and molec
2、ular disease6.Inborn error of metabolism and molecular disease 7.mt7.mt 8.8.PhmarcogeneticsPhmarcogenetics Nussbaum RL, et al. 张咸宁张咸宁,等等. Thompson http:/genome.cse.ucsc.edu Information on proteins: http:/ca.expasy.org Biomedical literature: www.ncbi.nlm.nih.gov/entrez/ Human gene mutation database:
3、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)
4、 ZHANG Xian-Ning, PhD Tel：13105819271; 88208367 Office: C303, Teaching Building 2014/09 Genotype: 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 varia
5、nt 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
6、 disease has been inherited. Proband: The family member who first bring a family to the attention of an investigator is proband. Pedigree symbols Symbols Commonly Used in Pedigree Charts Proband（先证者）（先证者）: III-5 Pedigree drawing software：Progeny, etc. Major Patterns of Monogenic Inheritance Patterns
7、 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 Dominant AD AD AD AD requires mutation in only one allele to produce dise
8、ase 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, neuro
9、fibromatosis, familial breast/ovarian cancer, myotonic dystrophy AD Huntington 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. Offspri
10、ng 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
11、 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-
12、35 Reduced penetrance 36-39 Fully penetrance 40 Anticipation 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 anticipat
13、ion 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
14、.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 ma
15、y 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
16、his brother, Bart. All three siblings chose molecular genetic testing following genetic counseling and neurologic evaluation. All have normal neurologic examinations. Clinical Case What do these results mean? Mary 38 CAG repeats Samuel 35 CAG repeats Alice 42 CAG repeats Bart John Mutable normal Mol
17、ecular Genetic Testing Diagnosis Samuel (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 sympt
18、omatic HD. Mary Samuel (30 y.o.) 35 CAG repeats Mutable normal allele Alice Mary (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. M
19、arys 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 repeats Reduced penetrance allele Samuel Alice Alice (42 repeats) is told that she has a full penetrance allele. Expans
20、ions 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. Mary Samuel Alice (29 y.o.) 42 CAG repeats Full penetrance allele HD gene-Hero! I
21、n 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 l
22、aboratories from various countries and officially designated HD. (Gusella et al.) Little:“Huntingtons disease: The end of the beginning” (Nature) Locations of Repeats Richards COL1A2, 7q22.1) -Locus heterogeneity bone fragility reduced life span short stature dentinogenesis hearing loss affects 1/10
23、 000 individuals OI type I Blue sclerae Near normal height Fractures Hearing loss Dominant inheritance OI type II Severe bone compression Soft calvarium Blue sclerae Perinatal death New in family OI type III Very short Marked and progressive deformity Blue or normal sclerae Dentinogenesis imperfecta
24、 Often non-ambulatory Often new in family OI 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 haploinsuffi
25、ciency germline mosaicism Genetic Basis of Osteogenesis Imperfecta Classic 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 mutati
26、on Eric 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
27、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
28、once again suffered abuse at the hands of his mother and her boy friend. EDS type I 4.5-year-old boy Unusual Features of Autosomal Dominant Inheritance 1. Reduced penetrance 2. Variable expressivity 3. High frequency of new mutations Autosomal Recessive(AR) AR AR AR AR requires mutation of both alle
29、les 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, phen
30、ylketonuria, cystic fibrosis, spinal muscular atrophy, Wilson disease AR 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 diseas
31、e 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
32、 body 1st identified Hb disease 1/600 African Americans HbS -CCT GTG GAG- -Pro Val Glu- HbA -CCT GAG GAG- -Pro Glu Glu- 6 6 Cystic 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
33、 (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
34、 - (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 a
35、nalysis. Science 245: 1073-1080. CF Other Examples of AR Disorders 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, d
36、etermined 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 clinica
37、lly 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 atr
38、ophy (SMA) Wilson disease: Cu toxicity, AR Wilson SAK. Brain, 1912; 34:295-507 Wilson disease:Before/After penicillamine therapy X-linked Recessive (XR) XR XR XR XR due to a recessive mutation located on the X- chromosome males predominantly or exclusively affected mothers are carriers no male-to-ma
39、le 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) deficiency XR XR Hemizygote: no corresponding loci on the Y chromosome, only one allele of each X chromoso
40、me locus. XR Duchenne 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
41、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
42、 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. DMD DMD: Gowers maneuver Genetics of DMD occurring
43、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 g
44、ene, 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 mb Other Examples of XR Hemophilia A: a classical example anti Hemophilia factor deficiency.
45、 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 f
46、orms, 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) X
47、D XD 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 pigmenti XD Examples of XD Disorders Vitamin D-resistant rickets: T
48、here 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
