* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Lctures Clinical genetics 1
Oncogenomics wikipedia , lookup
Nutriepigenomics wikipedia , lookup
Skewed X-inactivation wikipedia , lookup
Genome evolution wikipedia , lookup
Genetic testing wikipedia , lookup
Point mutation wikipedia , lookup
Gene therapy of the human retina wikipedia , lookup
History of genetic engineering wikipedia , lookup
Saethre–Chotzen syndrome wikipedia , lookup
Genetic engineering wikipedia , lookup
Site-specific recombinase technology wikipedia , lookup
Fetal origins hypothesis wikipedia , lookup
Y chromosome wikipedia , lookup
Artificial gene synthesis wikipedia , lookup
Gene therapy wikipedia , lookup
Neocentromere wikipedia , lookup
Behavioural genetics wikipedia , lookup
Gene expression programming wikipedia , lookup
Neuronal ceroid lipofuscinosis wikipedia , lookup
DiGeorge syndrome wikipedia , lookup
Public health genomics wikipedia , lookup
Population genetics wikipedia , lookup
X-inactivation wikipedia , lookup
Quantitative trait locus wikipedia , lookup
Genome (book) wikipedia , lookup
Designer baby wikipedia , lookup
Lectures Clinical Genetics Dr. Aneela Javed The Clinical Genetics course aims to: 1. Provide a programme of advanced study for graduates that will equip them for future careers in medical genetics and related areas; 2. Foster intellectual skills necessary to develop a critical and comprehensive understanding of the scientific principles, informatics and ethical frameworks that underlie the theory and practice of medical genetics; 3. Develop skills for the collection, analysis, interpretation and understanding of scientific data Course Contents: 1. The place of genetics in medicine 2. Mendel’s laws 3. Inheritance pattern principles and clinical examples 4. Chromosome structural abnormalities and clinical examples 5. Principles of multi-factorial disease 6. Allele frequency 7. Genetic linkage 8. Gene mapping 9. Mutagenesis and DNA repair 10. Mutations 16. Pedigree drawing 11. The molecular biology of 17. Risk assessment cancer 18. Dysmorphology 12. Familial cancers 19. Chromosome analysis 13. Immunogenetics 20. Biochemical diagnosis 14. Genetic disorders of the 21. Reproductive genetic counseling immune system 22. Prenatal sampling 15. Biochemical genetics 23. Clinical application of linkage 16. Clinical applications of 24. DNA profiling genetics 25. Management of genetic disease 26. Avoidance and prevention of disease 27. Ethical and social issues in clinical genetics Recommended Books: •New Clinical Genetics by Andrew Read, Dian Donnai, Scion Publishing Ltd, Bloxham, Oxford Shire, UK. •Clinical genetics: a short course by Golder Wilson, Volume 3, WileyLiss. •Genetics in Practice: A Clinical Approach for Healthcare Practitioners by Jo Haydon, Wiley-Blackwell. •Medical Genetics at a Glance, 2nd Edition by Dorian J. Pritchard, Bruce R. Korf, Wiley-Blackwell. •Essential Medical Genetics, Edition 6th Edition by Edward S. Tobias, Michael Connor, Malcolm Ferguson Smith, Wiley-Blackwell. Clinical Genetics The study of inheritance of a pathologic condition as well as genetic factors influencing its occurrence. • Interpretation and drawing pedigree • Modes of inheritance: 1- Autosomal 2- Sex linked 3 -Mitochondrial Inheritance 4 -Mosaicism • Penetrance and variable expression Exercises PEDIGREE A chart of an individual's ancestors used in clinical genetics to analyze Mendelian inheritance of certain traits/familial diseases. TOOL KIT FOR PEDIGREE ANALYSIS Pedigree interpretation How to write possible genotypes XY X Y XX X X Activity: Draw pedigree for following case Your patient, Anna, is 35 years old. She has a brother, Brad, who is 32. Anna and Brad are the only children of Charles, who died at 61 from cancer, and Nancy, who is alive and well at 57 years old. Anna is married to Don, who is 36, and they have identical 6-year-old twin boys, James and John. Brad and Linda have a 5-year-old daughter, Sarah, and a 2-year-old son, Michael. Brad and Linda are recently divorced. MODES OF INHERITANCE Autosomal 1-Autosomal dominant: (draw all three cases…father , mother or both affected) •A vertical pedigree pattern, with multiple generations affected •Each affected person normally has one affected parent •Each child of an affected person has a 1 in 2 chance of being affected •Males and females are equally affected and equally likely to pass the condition on (Huntington) MODES OF INHERITANCE 2-Autosomal recessive (draw all three cases…father , mother or both affected) •A horizontal pedigree pattern, with one or more sibs affected; often only a single affected case •Parents and children of affected people are normally unaffected •Each subsequent sib of an affected child has a 1 in 4 chance of being affected, 2/4 carriers •Males and females are equally affected •Affected children are sometimes the product of consanguineous marriages. In families with multiple consanguineous marriages, affected individuals may be seen in several generations MODES OF INHERITANCE 3-X-linked recessive ( father , mother or both affected) •A ‘knight’s move pedigree pattern- affected boys may have affected maternal uncles •Parents and children of affected people are normally unaffected. Never transmitted from father to son •Affects mainly males; females can be carriers, and affected males in a pedigree are linked through females, not through unaffected males • Subsequent brothers of affected boys have a 1 in 2 risks of being affected ; sisters are not affected but have 1 in 2 risk of being carriers. (Muscular dystrophy) RARE MODES OF INHERITANCE 4- X-linked dominant • Vague concept of heterozygosity in males n females, dominance n recessiveness are not prominent for X linked. X linked hypophosphatemia • Features very much similar to autosomal dominant pedigrees, except that all daughters and no sons of an affected father are affected • Condition is often milder and more variable in females than in males 5- Y-linked •A vertical pedigree pattern •All sons of an affected father are affected •Affects only males, mostly leading to infertility RARE MODES OF INHERITANCE 6-Mitochondrial 1- Matrilineal pattern of inheritance : passed on by the mother, but never by father, affect both sexes equally. Leber hereditary optic neuropathy affects mostly males. (2) Typical mendelian inheritance patterns (3) HETEROPLASMY: The proportion can vary between tissues and in the same tissue over time low penetrance and extremely variable expressivity. (4) Ova contain many mitochondria: therefore a heteroplasmic mother can have heteroplasmic children. RARE MODES OF INHERITANCE Mitochondrial Fletcher case pattern. initial hypothesis / a quick decider When individual pedigrees are checked the initial hypothesis is based on two questions: 1- does the pedigree show that the affected people have at least one affected parent. If yes the condition is most likely dominant. If no is recessive. 2- are there any gender effects? Does the condition affects both sexes and can it be passes on by parent of either sex to a child of either sex. If no gender effects condition is most likely autosomal. Male to male transfer is powerful pointer against X-linked inheritance as a father should never transmitt his X t o son. PENETRANCE The proportion or % of individuals with the relevant mutation who exhibit clinical symptoms. Both syndrome and different features of same syndrome, can have different penetrance. No-penetrance is pitfall in interpretation n counseling, a counselor should take care, refer molecular testing. Continuum of penetrance • Spectrum of characters and genes from 100% to nill •NEUROFIBROMATOSIS: mild to severe, 59exons so molecular testing/mutational analysis is not effective in most cases. MOSAICISM A person whose body contains two or more genetically different cell lines is called a mosaic. Difficulty in genetic counseling. For freshly arising mutations during mitosis and meiosis. Mosaicsm can be important under following conditions: (1) If the mutant cells have a tendency to grow and take over (2) If the mutation arose sufficiently early in embryonic development , The person may show features of milder disease phenotype or with a patchy distribution reflecting the distribution of mutant cells (3) Germ-line mosaicism (sperm or egg cells or their progenitors) is a major source of uncertainty and confusion in pedigree interpretation and genetic counseling. Clinical tests normal but children effected dominantly. Assignment 1- Identify the mode of inheritance/ Any comments 2- Assign genotypes 3- Risk of next child affected (arrowed person) should know: mitosis, meiosis, types of chromosomes, hetero n euchromatin, karyotype, etc Chapter 2 Why to study chromosomes: Infertility, recurrent miscarriages (50% aborted embryos have chr abnor),Prenatal screening to terminate the pregnancy, determine the chances of cancer. How to study chromosomes: sources 1-PBMCs 2-Chorionic villi 3-Amniotic fluid 4-Skin biopsies 5-Testicular biopsies Method: CHROMOSOMAL ABERRATIONS Random, though 70% ND at 1st meiotic in mother….WHY??? oogonia enter meiosis become oocytes, In foetal ovary ,oocytes arrested in the first meiotic prophase for decades females are born with a finite number of oocytes reenter meiosis only when they are ovulated in response to hormones. Over time, the quality of the oocytes may deteriorate ,abnormalities arise CHROMOSOMAL ABNORMALITIES 1-Numerical a) Errors of ploidy: wrong number of complete sets of chromosomes. Coz of nondisjunction, Usually die, can be seen in individual cells. b) Aneuploidy. Missing or extra chromosomes. Autosomal trisomies: all possible but 13 (patau syndr),18 (Edward syndr),21( Down syndr) ..guess why? Sex chromosomes: 45,X, females, turner syndr : 47, XXY, male, Klinifelters syndr, 47, XXX, females, lower IQ, 47,XYY, males, behavior problem, otherwise normal. c) Micro deletions and duplications: too small to be noticed on standard chr preps, lot of syndromes documented (box 2.4: p33) 2- Structural: Translocation : caused by rearrangement of parts between non-homologous chromosomes. balanced (in an even exchange of material with no genetic information extra or missing, and ideally full functionality) or unbalanced a) Robertsonian: two acrocentric chromosomes (13,14,15,21,22,Y), fuse near the centromere region, loss of the short arms, 45 chromosomes left, no direct effect on the phenotype (nucleolar organizer genes ,common to all acrocentrics plus variable copy number). b) But risk of unbalanced gametes lead to miscarriages or abnormal offspring. Robertsonian translocations of chr 21 have a higher chance of having a child with Down syndrome. Non-Robertsonian or Reciprocal translocation : • Exchange of material between non-homologous chromosomes, other then centromeres • Gametogenesis, or somatic cells Translocations can alter the phenotype is several ways: •Break within a gene destroying its function •Bringing genes under the influence of different promoters and enhancers , expression is altered. The t(8;14) translocation in Burkitt's lymphoma • breakpoint may occur within a gene creating a hybrid gene. an Nterminal of one protein coupled to the C-terminal of another. chronic myelogenous leukemia (CML) ……Philadelphia chromosome produces a compound gene (bcr-abl). (breakpoint cluster region…..Abelson) BCR-Abl transcript results in a protein that is "always on" or continuously activated, DELETIONS Types of deletion Terminal Deletion' - a deletion that occurs towards the end of a chromosome. Must be caped by telomere for stability….WHY??? Ring chr: epilepsy, dwarfism, mental retardation etc Interstitial Deletion - a deletion that occurs from the interior of a chromosome. microdeletion - a relatively small amount of deletion (up to 5kb that could include a dozen genes). Causes include Losses from translocation Chromosomal crossovers within a chromosomal inversion Unequal crossing over Breaking without rejoining DUPLICATIONS less deleterious rather imp for evolution. recombination is unequal, chromatids that are out of alignment, Retrotransposition. new gene carries inappropriate promoters at its 5' end (acquired from the 11-beta hydroxylase gene) that cause it to be expressed more strongly than the normal gene. The mutant gene is dominant: results in high blood pressure ,prone to early death from stroke. Fragile X Syndrome: CGG Huntington's disease ,CAG, which adds a string of glutamines (Gln) INVERSIONS when a single chromosome undergoes breakage and rearrangement within itself. Para or peri. may involve gene breakage, dif promotor, etc or no effect but this will create problems at homologous recombination, looped structure.