Lectures Clinical Genetics Dr. Aneela Javed. The Clinical Genetics course aims to: 1.Provide a...
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Transcript of Lectures Clinical Genetics Dr. Aneela Javed. The Clinical Genetics course aims to: 1.Provide a...
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
11.The molecular biology of
cancer
12.Familial cancers
13.Immunogenetics
14.Genetic disorders of the
immune system
15.Biochemical genetics
16.Clinical applications of
genetics
16.Pedigree drawing
17. Risk assessment
18.Dysmorphology
19.Chromosome analysis
20.Biochemical diagnosis
21.Reproductive genetic
counseling
22.Prenatal sampling
23.Clinical application of linkage
24.DNA profiling
25.Management of genetic
disease
26. Avoidance and prevention of
disease
27. Ethical and social issues in
clinical genetics
Pedigree
Inheritance modes
1. Autosomal
2. X linked
a) Dominant
b) Recessive
3. Y linked
4. Mitochondrial
5. Mosaicism
6. Penetrance
Major chr abnormalities and
their clinical relevance
1. Numerical
2. Structural
Course Contents:
WHY AND HOW TO STUDY CHROMOSOMES
Techniques 1. Karyotyping2. Hybridization3. qPCR4. RNA testing5. Protein testing6. CHR painting
HOW DO GENES WORK
1. Gene structure2. Splicing 3. Translation 4. Beyond translation5. epigenetics
EPIGENETICS:
1. Dosage compensation2. Imprinting3. Imprinting disorders4. DNA methylation
MUTATION ANLYSIS:
1. Causes2. Effects of
mutation3. Mutation
detection4. Clinical
examples
Prenatal sampling1. Invasive and non invasive tech2. Qualifying risks3. Ethical issues
Multifactorial disorders•Population genetics
CASE STUDIES
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, Wiley-Liss.•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
• Interpretation and drawing pedigree
• Modes of inheritance:
1- Autosomal
2- Sex linked
3 -Mitochondrial Inheritance
4 -Mosaicism
• Penetrance and variable expression
Exercises
The study of inheritance of a pathologic condition as well as genetic factors influencing its occurrence.
A chart of an individual's ancestors used in clinical genetics to analyze Mendelian inheritance of certain traits/familial diseases.
PEDIGREE
TOOL KIT FOR PEDIGREE ANALYSIS
Pedigree interpretationHow to write possible genotypes
XXXY
X Y 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.
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
Autosomal
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)
MODES OF INHERITANCE
4- X-linked dominant
• Vague concept of heterozygosity in males n females, dominance
n recessiveness are not prominent for X linked. E.g 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
RARE MODES OF INHERITANCE
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.
Leber’s hereditary optic
neuropathy (LHON) or Leber optic
atrophy is amitochondrially inherited
(transmitted from mother to offspring)
degeneration of retinal ganglion cells
(RGCs) and their axons that leads to an
acute or subacute loss of central vision;
this affects predominantly young adult
males. However, LHON is only
transmitted through the mother as it is
primarily due to mutationsin the
mitochondrial (not nuclear) genome and
only the egg contributesmitochondria to
the embryo.
ROS produced through the process of oxidative phosphorylation by the electron transport chain in mitochondria. NADH dehydrogenase mutations of complex I may increase the leaking of electrons from the chain, leading to increased accumulation of ROS, oxidative stress, and RGC death.
(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.
Fletcher case pattern.
RARE MODES OF INHERITANCE
Mitochondrial
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.
initial hypothesis / a quick decider
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.
PENETRANCE
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.
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.
MOSAICISM
Assignment
1- Identify the mode of inheritance/ Any comments 2- Assign genotypes3- Risk of next child affected (arrowed person)