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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.