MSc in Medical Genetics

The University of Glasgow
Department of Medical Genetics
 

Learning Objectives

The learning objectives are things students are expected to be able to do at the end of the course. Most, but not all, of these will be covered in traditional lectures, tutorials and practicals in terms 1 and 2. It is each student's responsibility to cover these objectives, during individual and group study, using the learning resources available in the department.

Terms 1 and 2: Traditional teaching and practical work.

• Human cytogenetics
• Diagnostic molecular genetics
• Population, screening and biochemical genetics
• Clinical aspects of medical genetics
• Problem sessions

• Problem Based Learning: students identify their own learning objectives in order to solve problems from the clinics and laboratories. 

Term 4: Individual work.

• Dissertation

Human Cytogenetics

Introduction to cytogenetics.

• define the objectives of a clinical cytogenetics service
• describe the various tissues which may be used to produce chromosome preparations
• describe the method for obtaining chromosome preparations from a blood sample

Safety in the genetics laboratory.

• describe safe laboratory practice
• state hospital policy on segregation and disposal of waste.
• describe the principles of COSHH regulations affecting your work.

Looking at chromosomes.

• be able to identify features of un-banded chromosomes.
• discuss the advantages of different banding techniques.
• describe banding nomenclature (ISCN).
• describe several cytogenetic polymorphisms.
• recognise and describe the significance of a fragile site.
• know when FISH techniques are an appropriate investigation.

Mitosis and meiosis.

• state the principles of the somatic cell cycle.
• describe the processes of mitosis and meiosis.
• know the stages in these processes where common abnormalities can occur.

Chromosome structural abnormalities.

• describe the range of balanced and unbalanced rearrangements which may occur.

• understand the effect of unbalanced abnormalities on the phenotype.

• understand the prognostic implications of these rearrangements.

Meiosis in structural abnormalities.

• describe the pairing configuration of structurally rearranged chromosomes during meiosis.
• describe the types of segregation possible from such pairing.
• be able to identify associated risks to carriers of such rearrangements.

Uni-parental disomy.

• describe the genetic mechanisms which result in uni-parental disomy.
• discuss the genetic consequences of uni-parental disomy.
  • e.g. abnormal genomic imprinting.
  • homozygosity for recessive mutations.
  • father to son transmission of X chromosome.
• discuss the clinical consequences of uni-parental disomy.

• discuss the clinical indications of prenatal diagnosis.
• discuss the advantages and disadvantages of  the obstetric procedures used to obtain samples for prenatal diagnosis
• describe the methodology of obtaining a karyotype from a prenatal diagnosis sample.
• understand the embryology of chorionic villi.

The future of prenatal diagnosis.

• be able to discuss the advantages and disadvantages of the following sampling methods:
  • early amniocentesis
  • coelocentesis
  • transcervical trophoblasts
  • fetal cells in the maternal circulation
  • Pre-implantation Genetic Diagnosis
• be able to discuss the application of the following techniques to the above sampling methods.
  • cytogenetics
  • FISH techniques
  • PCR
  • CGH

Molecular cytogenetics: FISH technology and application.

•  Describe the process of fluorescence in-situ hybridisation.

•  Identify the main service applications of FISH in cytogenetics.

• Identify probe types appropriate to specific diagnostic situations.

• Discuss the application of FISH in the diagnosis of micro-deletion syndromes.

Developments in molecular cytogenetics.

•  Discuss the basic concepts of the following FISH technologies:

  • Comparative Genomic Hybridisation (CGH)

  • Matrix CGH

  • Primed in situ Labelling (PRINS)

  • FiberFISH

  • Multiplex FISH

  • Cobra

  • Multi probe devices

  • Chromosome bar coding

•  Identify areas of medical genetics which might benefit from the application of these developments.

Cytogenetics of cancer: haemopoesis.

• describe the ordered production of normal blood cells.

• describe the cellular origins of the common leukaemias.

• understand the classification of leukaemias.

• describe the laboratory techniques used to produce chromosome preparations from bone marrow samples.

Acquired chromosome changes in human leukaemias.

• discuss the acquired chromosome changes and their relevance to diagnosis, prognosis and disease progression.
• understand the significance of some common specific chromosome abnormalities in:
  • acute leukaemias
  • chronic myeloid leukaemia CML
  • MDS
  • MPD
  • secondary and therapy related disorders.
• discuss bone marrow transplant techniques and the role of cytogenetics.

Diagnostic Molecular Genetics

Introduction: the tools of the molecular geneticist.

• discuss the use of restriction enzymes, cloning vectors and the polymerase chain reaction (PCR).
• define and identify the role of linked markers and gene probes.

Principles of genotype analysis: DNA linkage analysis.

• discuss risk assessment of X-linked recessive, autosomal recessive and autosomal dominant disorders using linked markers.
• infer marker alleles in family members unavailable for testing to enable counselling of descendents.
• discuss the limitations of a marker analysis.
• define gonadal mosaicism and discuss its effects on genetic analysis and testing.

Mutation detection strategies in Duchenne and Becker muscular dystrophy (DMD/BMD)

• know the value of serum creatine kinase levels to the interpretation of DNA data.
• describe the various types of mutations causing DMD/BMD.
• discuss methods for detection of mutations and their limitations.
• discuss in-frame and frame shift deletions with respect to severity of phenotype
• discuss the advantages and disadvantages of the protein truncation test compared with other DNA based methods of mutation detection.

Linkage, recombination and lod Scores.

• describe genetic recombination and discuss its effects on genetic analysis and testing.
• understand linkage disequilibrium!
• be able to calculate lod scores.
• be able to interpret lod scores.

Genome organisation and mutations.

• Describe the structure of genes.

• Describe RNA transcription and processing.

• Discuss the common mutation types with clinical examples:

  • Deletions

  • Insertions and duplications

  • deamination of 5-methyl cytosine

  • base substitutions

  • trinucleotide repeat expansions.

• identify factors which can cause misinterpretation of DNA data e.g. mistaken paternity, gonadal mosaicism, and laboratory error.

Diagnostic applications of the polymerase chain reaction (PCR).

• describe the PCR reaction.
• discuss the design of PCR primers.
• describe Multiplex PCR and identify it’s uses.
• describe the amplification refractory mutation system (ARMS) and identify it’s uses.
• discuss the methodology and application of the following:

  • Reverse transcriptase PCR

  •  SSCP

  • heteroduplex analysis

  • DGGE

  • chemical cleavage of mismatched base pairs

  • DNA sequencing

The thalassaemias

• describe the clinical features of the thalassaemias.
• understand the structure of haemoglobin.
• discuss the molecular pathology of the thalassaemias.
• describe the techniques of haematological and molecular diagnosis.
• discuss population strategies for reducing the incidence affected homozygotes.

Cystic fibrosis.

• describe the clinical features of  cystic fibrosis.
• discuss the spectrum of pathological mutations.
• discuss the effect of genotype on phenotype.
• understand the ARMS analysis as a strategy to detect the commoner mutations.
• discuss strategies for carrier screening.

Disorders caused by triplet repeat expansions.

• describe the phenotypes of the common triplet repeat disorders.
• understand the underlying mechanism for apparent non Mendelian inheritance in families segregating for these disorders.
• describe methods of molecular analysis of triplet repeats.

Micro-deletion  syndromes.

• describe the clinical features of some of the common micro-deletion syndromes.
• discuss methods of molecular and molecular cytogenetic analysis of micro-deletion syndromes.
• understand the effects of genomic imprinting on the phenotype of micro-deletion syndromes such as Angelman syndrome and Prader-Willi syndrome.

Population screening and biochemical genetics

Principles of population screening.

• describe the criteria to be met before introducing a screening programme.
• outline the aims of various types of screening programme: Prenatal (e.g. neural tube defects), Carrier (e.g. cystic fibrosis), Neonatal (e.g. phenylketonuria), Adult (e.g. cervical cancer)
• discuss the sensitivity and specificity of various screening tests
• describe the evaluation of a screening programme.

Screening and prenatal diagnosis of neural tube defects.

• describe the main types of neural tube defects, open and closed.

•  discuss the use of amniotic fluid AFP and AChE in the prenatal diagnosis of NTD.

•  discuss the use of maternal serum AFP in population screening for NTD.

•  use multiples of the median to identify at risk population sub groups.

•  describe the role of ultrasound in prenatal diagnosis and screening of NTD.

Markers, populations and dosage mapping.

• define and discuss examples of human polymorphism (e.g.. blood groups, red cell enzymes, serum proteins)
• use the Hardy-Weinberg principle to calculate allele frequencies
• describe the use of deletions and duplications in human gene mapping
• Describe the use of chromosomal deletions and duplications in human gene mapping

Screening for Chromosome abnormalities I.

• describe the birth incidence of Down’s syndrome according to maternal age.

• discuss the use of maternal serum AFP in screening for Down’s syndrome pregnancies.

•  discuss the use of maternal serum hCG in screening.

•  calculate  combined risks from AFP, hCG and maternal age.

Screening for Chromosome abnormalities II.

• discuss the usefulness of alternative maternal serum markers in screening for Down syndrome: UE3, FbhCG, FahCG, SP-1, Inhibin, Progesterone, hPL.

• discuss the use of biophysical markers and urinary markers in screening for Down syndrome.

• describe fetal abnormalities associated with serum marker variation: e.g. trisomy 18; triploidy.

Inborn errors of metabolism I.

• describe the classification of inborn errors of metabolism.

• discuss diagnosis, prenatal diagnosis and carrier detection and the importance of diagnosis in the index case

•  assess choice of tissues and advantages and disadvantages for PND

•  discuss pitfalls in interpretation of results, confirmation of diagnosis, use of family studies.

Inborn errors of metabolism II, biochemical data interpretation.

• describe the use of quantitative estimation of gene products to determine genotype status in inborn errors of metabolism.
• use distribution statistics to describe levels of enzyme activities.
• use population distribution curves to estimate carrier risks.

Statistics I.

• describe experimental design.

•  use tables, bar charts, scatter plots for data presentation.

• summarise data using median, mean, standard deviation and centiles.

• discuss accuracy and precision and its impact on biochemical data.

Statistics II.

• describe the meaning of probability and the null hypothesis.

• test for differences between data sets using t test, Mann Whitney test, c² test.

• describe correlation, regression and confidence intervals.

Practical aspects of screening.

• describe the quantification of markers by RIA, IRMA, ELISA.

• describe the parameters which affect efficacy of analytes used in screening.

• discuss practical aspects of setting up a population screening programme: population size, education, information, counselling, equipment etc.
• describe the effect of maternal factors and pregnancy complications on the use of maternal serum markers for screening.
• discuss the essential value of audit of the service and and research and development in screening programmes.

First trimester screening.

• describe differences in marker levels in Down’s syndrome and trisomy 18 pregnancies between first and second trimesters.
• describe appropriate first trimester markers and marker distributions in affected pregnancies.
• discuss the role of ultrasound markers in screening in the first trimester.
• discuss practical considerations for a routine first trimester screening program.

Mechanisms of marker variation.

• describe production, secretion, regulation and turnover of placental and fetal markers.
• understand the dynamics of interchange between fetal and maternal compartments.
• describe the variation in marker levels in fetal serum, amniotic fluid and maternal serum in normal and Down’s syndrome pregnancies.
• describe AFP levels in fetal and placental tissues from Down’s syndrome pregnancies.
• describe changes in hCG production in Down’s syndrome placentas.
• discuss endogenous levels of other markers of Down’s syndrome in fetal tissues.

Clinical aspects of medical Genetics

Genetic counselling.

• describe the organisation of a genetic counselling service.
• draw family trees.
• identify the important features of a good referral letter.
• describe the stages in the process of genetic counselling.
• write a straightforward summary letter to a patient.

Practical aspects of communicating with patients.

• describe pitfalls in communication with patients.
• be aware of cultural differences which can affect communication.
• identify and interpret common features of body language seen in the clinic.
• discuss potential problems in communication during pre and post termination counselling.

Speaking at a scientific meeting.

• be able to communicate your ideas clearly at a meeting of scientific and medical colleagues.
  • preparation: date, time, place, audience, length of presentation, structure.
  • making slides overheads and computer slides: estimating number, content – words, graphs, tables, other considerations. 
• give a good presentation: rehearsal, relating to audience, use of pointers, staying within allotted time.
• be able to answer questions.

Clinical aspects of prenatal diagnosis.

• identify the indications for prenatal diagnosis
• describe the clinical methods and complications of prenatal diagnosis
• identify the issues that need to be considered during counselling prior to PND.
• discuss ethical and emotional aspects of termination of pregnancy for genetic reasons.

Pedigree analysis of single gene disorders

• describe features of patterns of inheritance seen in pedigrees
• identify the mode of inheritance in pedigrees
• identify the recurrence risk for individuals in pedigrees.

Clinical aspects of cystic fibrosis.

• describe the clinical features of CF, DM and HD
• discuss the issues that need to be considered during counselling of affected families particularly with respect to pre-symptomatic testing in DM and HD.

Clinical aspects of  myotonic dystrophy.

• describe the clinical features.
• discuss the molecular basis of myotonic dystrophy.
• discuss the issues that need to be considered during counselling of affected families particularly with respect to pre-symptomatic testing.
• discuss the medical management and follow up of patients with DM.
• discuss the rationale and role of care pathways.

Clinical aspects of Huntington disease.

• describe the clinical features.
• discuss the issues that need to be considered during counselling of affected families.
• differentiate between diagnostic and pre-symptomatic testing.
• discuss the factors that need to be considered prior to pre-symptomatic testing.
• discuss the follow up and support of affected families

Clinical aspects of neurofibromatosis.

• describe the clinical features.
• discuss the medical management and follow up of patients with DM.
• discuss the rationale and role of care pathways.

Clinical aspects of Fragile X syndrome.

• describe the clinical features of Fragile X syndrome.
• describe how the pattern of inheritance can differ from that seen in other classical X-linked recessive disorders such as DMD and identify individuals at risk in affected pedigrees
• understand the molecular basis of the non Mendelian aspects of transmission of Fragile X syndrome.
• discuss the issues that need to be considered during counselling of affected families.

Clinical aspects of Duchenne and Becker muscular dystrophies.

• describe the clinical course of DMD/BMD
• discuss genotype/phenotype correlation in DMD/BMD
• discuss the effects of the disorder on other family members
• identify the issues that need to be considered during counselling of affected families.

Interpretation of DNA data in clinical situations.

• identify factors which can cause misinterpretation of DNA data e.g. mistaken paternity, gonadal mosaicism, and laboratory error.
• correctly interpret a number of problem pedigrees.

Introduction to Bayes theorem.

• define and identify prior and posterior genetic risks.
• use Bayes theorem to calculate genetic risks from pedigree information.
• use Bayes theorem to calculate genetic risks incorporating conditional DNA linkage information.
• identify situations where Bayes theorem is not necessary for risk calculation.
• identify situations where Bayes theorem is necessary for risk calculation.

Using serum creatine kinase (CK) in DMD carrier risk calculations.

• use normal and obligate carrier distribution curves to calculate a conditional likelyhood ratio.
• incorporate carrier likelyhood ratios based on CK levels into Bayes calculations.
• use Bayes theorem to calculate DMD carrier risks using pedigree, DNA and biochemical risks.

Advanced Bayes calculations.

• calculate prior risks in non lethal x-linked conditions eg haemophilia and BMD
• incorporate conditional risks from clotting studies in families with haemophilia
• use pedigree information from sibs, nephews and nieces to calculate prior risk in x-linked disorders such as DMD, BMD and haemophilia.

Clinical aspects of micro-deletion syndromes.

• recognise the main clinical features of Prader Willi, Angleman, velocardiofacial/di George and Williams syndromes.
• discuss appropriate methods of investigation. 
• understand the effects of parental origin and genomic imprinting on the phenotype.
• discuss the issues that need to be considered during counselling of affected families.

Genetic counselling in families with structural rearrangements

• identify at risk individuals from the pedigree.
• discuss the issues that need to be considered during counselling.
• identify the most suitable methods of prenatal diagnosis for those who wish it.
• describe strategies for contacting relatives
• discuss ethical problems relating to consent to contact relatives.

Sex chromosome abnormalities.

• identify numerical and structural abnormalities.
• correlate genotype with phenotype.
• describe the principle clinical features and recurrence risks of the common sex chromosome abnormalities.
• discuss the investigation and management of sex chromosome abnormalities.

Dysmorphology and clinical features of chromosome abnormalities.

• identify common dysmorphic features.
• discuss the common aneuploidy syndromes in man.
• describe the aetiology of Down syndrome and Turner syndrome.
• describe the clinical features of trisomy 21, 18 and 13.

Using internet resources to access information about genetic disorders.

• use a search engine to find relevant sites.
• use On line Mendelian Inheritance in Man (OMIM) to search and access genetic information.
• find and review patient "self help" sites.
• discuss limitations of data obtained from various sources.

The diagnosis and genetic management of dysmorphic syndromes.

• describe common dysmorphic features
• look for and identify additional features in common presentations such CHD, CLP and NTD
• use a computer database such as the London Dysmorphology Database to assist in the diagnosis of a dysmorphic syndrome.
• discuss the issues that need to be considered during counselling of affected families both when a diagnosis is made and when the syndrome remains undiagnosed.

Brain malformation syndromes and mental retardation.

• review brain development.
• describe features of common syndromes.
• discuss appropriate methods of investigation and diagnosis.

Multifactorial genetics.

• discuss examples of human continuous and discontinuous multifactorial traits.
• describe the use of twin concordance studies in determining the genetic component of multifactorial disorders.
• calculate the proportion of genes shared by people with different degrees of relationship.

Neural tube defects.

• describe the clinical features of the neural tube defects
• identify genetic syndromes associated with neural tube defects
• discuss the effects of the disorder on other family members
• discuss the issues that need to be considered during counselling of affected families.

Talking to parents about congenital malformations.

• discuss the incidence of congenital malformations.
• describe some of the commoner malformation syndromes.
• be aware of the issues that need to be considered when talking to parents whose baby has been born with an unexpected malformation.
• discuss recurrence risks and prognosis in appropriate language  for parents.

Cancer genetics.

• describe the key features of common cancer syndromes.
• identify those features of a pedigree or cancer which suggest a high genetic risk.
• discuss the molecular mechanisms of example genetic cancer syndromes.
• discuss the molecular strategies for mutation screening in affected families.
• discuss the extent and limitations of genetic testing in a number of familial cancer syndromes.

An approach to families with cancer.

• know how a cancer genetics clinic is organised
• identify individuals at risk in a pedigree.
• be aware of the use of computer programs and other methods for calculating genetic risks.
• discuss the implications of  pre-symptomatic testing in cancer families
• discuss the options for those found to be at high risk of familial cancer.

Ethics of genetic testing.

• discuss ethical issues relating to genetic screening programmes
• discuss ethical issues relating to testing of individuals:
  • presymptomatic testing.
  • genetic testing of children.
  • genetic testing of people with learning difficulties.
• discuss ethical issues relating to confidentiality and consent with respect to genetic testing.
• discuss ethical issues relating to practical genetic counselling in different countries and cultures.
• discuss ethical issues relating to the acquisition, use and storage of patient samples for research.

Gene therapy.

• discuss the criteria involved in a gene therapy protocol.

• understand the limitations and practicalities of gene transfer in dominant and recessive disorders.

• be aware of safety and ethical issues
• understand the implications of somatic vs. germ-line gene therapy.
• discuss advantages and limitations of different gene transfer systems:
  • naked DNA
  • antisense
  • chimeraplasts
  • liposomes
  • viral vectors
  • stem cells

The future of genetics.

• have an open, enquiring and critical mind!

Problem sessions

• record a pedigree.

• identify patterns of inheritance.

• identify individuals at risk.

• calculate risks from the pedigree.

• know when to use Bayes theorem in risk calculation.

• use Bayes theorem to interpret pedigree, DNA and biochemical risks.

• report a genetic risk in a format appropriate for patients.

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