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2008
GENETICS
Principles
 Each Human cell has
 46 chromosomes = 23 pairs
 Each pair consists of 1 paternal and 1 maternal
chromosome
 2 genes at equivalent loci each coding for an
individual polypeptide
Principles
 Gametes (ova/sperm) has only 50% of parents
genetic constitution
 The particle randomly selected is one of the 2
genes at each loci
 Heterozygote = 2 different allele (genes) at the
same locus
 Homozygote -= 2 identical alleles at the same
locus
Classification of diseases
 Diseases can be classified from
defects in
 Whole chromosomes – either
number or form
 Individual genes
 Lots of genes and/or the
environment
Autosomal disorders
 44 autosomes = 22 homologous pairs
 1 pair sex chromosomes
 Genes have strict order on each autosome
 Each gene occupies a distinct locus in unison
with its counterpart of maternal/paternal
origin
 Alleles are alternative genes that have arisen
by mutation
Autosomal disorders
 If both members of a gene pair are
identical then the individual is
homozygous
 If both members are different then
the individual is heterozygous
 Gene specified characteristics are
called traits
Autosomal disorders
 3 types of autosomal disorder
 Autosomal dominant – trait is seen in
heterozygote Aa and homozygote AA
 Autosomal recessive – trait is only seen in
homozygote aa
 Autosomal co-dominant – effect of both alleles
seen in heterozygote AB
Types of autosomal
inheritance
 Autosomal dominant inheritance
 Disorder manifest in both homo and heterozygote
 Both sexes can be affected but their can be
different degrees of severity = variable
expression between individuals
 Rarely an individual with a mutant gene may have
a normal phenotype = non penetrance the gene
and trait may still be transmitted to the offspring
Autosomal dominant disorders
• 2,200 dominant disorders known
– Dominant otosclerosis
–
–
–
–
–
–
–
3/1000
Familial hypercholesterolemia
2/1000
Adult polycystic kidney disease
1/1000
Multiple exostoses
0.5/1000
Huntingdon’s disease
0.5/1000
Neurofibromatosis
0.4/1000
Myotonic dystrophy
0.2/1000
Polyposis coli
0.1/1000
Autosomal recessive
disorders
•
•
•
•
•
•
•
•
Only appears in homozygote
Both parents usually heterozygote carriers
They are not affected by the disease
Incidence should be 1 in 4 of offspring
Affects each sex equally
Very little variability of expression
Parental consanguinity
A few are inborn errors of metabolism with
defective enzymes
Autosomal recessive
disorders
 Some are associated with ethnic
groups
 beta thalassaemia
Italians
 Sickle cell disease
West Indians
 Cystic fibrosis
Cypriots, Greeks,
Africans, Blacks,
Caucasians
Autosomal recessive
disorders
 14,000 autosomal recessive traits known
 Cystic fibrosis
 Recessive mental retardation
 Congenital deafness
 Phenylketonuria
 Spinal muscular atrophy
0.5/1000
0.5/1000
0.2/1000
0.1/1000
0.1/1000
Autosomal co-dominant
inheritance
 Can detect either or both of two alleles in an
individual
 The fragments can be followed through the
family tree
 Human blood groups ABO, duffy, kell, rhesus
exhibit this form of inheritance
Autosomal co-dominant
inheritance
 ABO blood groups
 If parents both AB then
 Get offspring who are A, AB, B
 But the ratio is 1(A) : 2(AB): 1(B) phenotype
 If one allele is dominant and the other recessive
would get 3:1 ratio
Chromosomal disorders
 If mutations large enough to be seen
under light microscope they are called
chromosomal disorders
 Divided into structural and numeric
disorders
 The smallest alteration to a
chromosome that is visible is 4x106
base pairs
Chromosomal disorders
 Affect 7.5% of all conceptions but due to
miscarriage only affect 0.6% of live births
 60% of spontaneous miscarriages have
chromosomal abnormalities
 Commonest type of abnormalities are
trisomies (Down’s, Edward’s), 45 (Turner’s), x
or triploidy
Chromosomal disorders
 Disorders result from germ cell
mutations in parents that have been
passed onto the sex chromosomes or
autosomes in the affected individual
 Arise out of somatic mutations in the
generation affected
Chromosomal disorders
 Autosomal chromosome
disruptions are more serious than
sex chromosomes disruptions
 Deletions are more serious than
duplications
Chromosomal disorders
 Numeric disorders









92
69
47
47
47
47
47
47
45
xxyy
xyy
xx (21)
xy (18)
xx (16)
xx (13)
xxy or xxxxy
xxx
x
tetraploidy
triploidy
trisomy 21
trisomy 18
trisomy 16
trisomy 13
Klinefelters
trisomy x
Turner’s syndrome
Chromosomal disorders
 Aneuploidy
 Exists when the chromosome number is not 46
but not a direct multiple of the haploid number 23
 Caused by delayed movement of chromatid
in the anaphase or non disjunction of
chromosomes in metaphase
 Occurs with increasing frequency with
 Maternal age
 Maternal hypothyroidism
 During recent radiation or viral illness
Chromosomal disorders
 Polyploidy
 Occurs with a complete extra set or sets of
chromosomes
 Triploidy arises from
 Fertilisation with 2 sperm or failure of one of the
maturation divisions of the egg or sperm so
producing a diploid gamete 69 xxy is the
commonest
 Tetraploidy is due to failure of first zygotic
division
Chromosomal disorders
 Trilpoidy
 69 xxy or more rarely xxx
 2% of all conceptions usually leads to miscarriage
 If carries on to term
 Low birth weight
 Disproportionally small head to trunk
 Syndactyly
 Multiple congenital abnormalities
 Large placenta with hydatidiform like changes
Chromosomal disorders
 Tetraploidy
 Describes a situation where the
genotype is 96 xxyy or some other
combination of sex chromosomes
 Is rapidly fatal rarely survives to
term
Chromosomal disorders
 Trisomy
 Is having 3 copies of a chromosome
 Caused by failure of disjunction during meiosis
with unequal separation of the chromosome
between the gametes
 Most are rapidly fatal only trisomy 21 survives
beyond 1yr
 Trisomy 13 – Patau’s syndrome severe mental
retardation
 Trisomy 18 – Edward’s syndrome
Chromosomal disorders
 Sex chromosome abnormalities
 Turner’s




xo
short stature webbed neck
Triple x
xxx developmental delay tall
Double y
xyy
tall fertile psychiatric illness
Klinefelter’s xxy tall infertile early germ cell
atrophy poor secondary sexual characteristics
Fragile x
dominant x linked gene with 50%
penetrance in females developmental delay
Chromosomal disorders
 Structural disorders
 Arise from chromosomal breakage, once broken
attempted repair may rejoin 2 unrelated parts of
the chromosome
 Breakage facilitated by
 Ionising radiation
 Mutagenic chemicals
 Some rare inherited conditions
Chromosomal disorders
 Recognised structural abnormalities
 Translocation the transference of material
between chromosomes. Carriers with balanced
translocations are not affected but offspring are
 Deletion this occurs at both ends of a
chromosome can lead to ring chromosomes
 Duplication of a section of a small section of
chromosome often with little harmful
consequence
Chromosomal disorders
 Recognised structural abnormalities
 Inversion – breakage at 2 ends of a chromosome
with rotation and rejoining of the part in between
so that it lies the wrong way round
 Isochrome – deletion of one arm of a chromosome
with duplication of the other arm
 Centric fragments – small remaining material
after translocation
Chromosomal disorders
 Chromosomal deletion disorders
 Angleman syndrome
 Prader-willi
 Cri du chat
Chromosomal disorders
 Other disorders
Multifactorial disorders
 Phenotype is determined by the actions of
multiple genetic loci and the environment
 Risk in these families is higher than normal
population it decreases with distance from
affected individual
 Twin concordance and family correlational
studies are required if multifactorial
inheritance is suspected
Multifactorial disorders
 Examples
 Spina bifida
 Geographical differences indicate celtic descent
 Seasonal variation and greater incidence in lower
social class indicate an environmental influence also
happening
 Cleft palate and lip
 CDH
 Diabetes
 epilepsy
Multifactorial disorders
 Examples
 Hyperthyroidism
 Multiple sclerosis
 Psoriasis
 Pyloric stenosis
 Schizophrenia
 Alzheimer’s
Sex linked disorders
 Women have two x chromosomes one from
each parent one of which is inactivated at
random
 Males have only one x chromosome
 X linked disorders can be dominant or
recessive. In dominant disorders they are
present in women as well as men
Sex linked disorders
 Recessive x linked disorders
 Only males affected
 No variation of expression disease always follows
predictable course
 Heterozygous females are not affected but carry
the gene
 Rarely occurs in female only if faulty inactivation
of the x chromosome
Sex linked disorders
 290 recessive x linked diseases are known
 Red green colour blind
 Fragile x
 Duchenne muscular dystrophy
 Becker muscular dystrophy
 Haemophilia A factor 8
 Haemophilia B factor 9
 X linked agammglobulinaemia
Sex linked disorders
 X linked dominant disorders
 Expressed in both sexes but more common in




females due to greater number of x chromosomes
Females may be homozygous or heterozygous
Males can only be heterozygous
Positive father will give trait to all his daughters
but none of his sons
Positive mother will give trait to half her sons and
half her daughters
Sex linked disorders
 X linked dominant disorders
 The trait is uniform seriousness in males
 In females it has variable seriousness
 Examples – very few known disorders
 Xg blood group
 Vitamin D resistant rickets
 Rett’s syndrome
Digenic disorders
 In these disorders two genes interact to
produce the phenotype
 Mode of inheritance is often simple
mendelian but with another gene interfering
to modulate the severity of the disease
 Examples
 Cystic fibrosis
 Limb girdle dystrophy
Familial cancers
 Examples
 Breast
 Ovarian
 Colorectal
 5-10% of new cases are caused by dominantly
inherited single gene mutations
 Combinations of lower penetrance genes also
contribute to a significant portion of family
histories
Familial cancers
 Features suggestive of inherited cancer
 High incidence in family in closely related individuals
 Early age of onset
 Multiple primaries in an individual (rockenbach)
 Certain cancer combinations
 Breast and ovary
 Breast and sarcoma
 Colorectal, uterine, ovarian and stomach
 Ethnicity – Ashkenazi Jews high incidence of 3
common breast and ovarian cancer founder mutations
Familial cancers
 Who to refer with FH breast and ovarian
cancer
 Mother or sister breast ca < 40yrs
 Mother or sister bilateral breast ca any age
 Father or brother with breast ca any age
 Mother or sister with breast and ovarian ca any
age
 One close relative with breast ca < 50 and relative
with ovarian caany age same side of family
Familial cancers
 FH breast and ovarian ca who to refer
 Two close relative breast ca any age
 Two close relative ovarian ca any age
 Three or more close relative with breast
ca, ovarian ca or both on the same side
of the family at any age
Familial cancers
 Who to refer colorectal cancer
 1 first degree relative CRC < 45yrs
 1 first degree relative who has 2 separate or
multiple CRC or two associated ca – CRC,
endometrial, ovarian, small bowel, ureter or renal
pelvis.
 1 first degree relative with more than 1 bowel
polyp < 40 which is tubulovillous, dysplastic, or an
adenoma > 10cm
Familial cancers
 Who to refer CRC cancers
 1 first degree relative with FAP of FH of FAP
 1 parent with multiple colorectal polyps >100
 2 close relatives who are first degree relatives
to each other can include both parents with
average age < 70 of CRC
 2 close relatives who are first degree relatives
to each other on same side of family with
associated cancers age < 50
Familial cancers
 Who to refer CRC
 3 close relatives on same side of family with an
associated tumour
Familial cancers
 High risk pedigrees
 4 close relatives with breast, ovarian, or
both any age
 3 close relatives with breast ca average age
< 60
 2 close relatives with breast ca average < 50
 2 close relatives ovarian ca any age
 Known families of carriers of BRCA1,
BRCA2
Familial cancers
 High risk pedigrees
 3 close relatives CRC or 2 with CRC and one
associated cancer in at least 2 generations. 1 must
be under 50 at diagnosis and one should be first
degree relative of the other 2
 Known gene carriers of hereditary non polyposis
colon ca FAP or relatives of known affected family
 All others are moderate risk
Familial cancers
 Moderate risk pedigrees are normally
managed in secondary care
 Breast ca
 Annual mammograms from age 40-50 then will
enter national 3 yrly scheme
 CRC
 Offered colonoscopy frequency varies
Familial cancers
 High risk pedigrees
 Normally seen and counselled by regional genetic
centre
 Breast
 Annual mammograms
 If BRAC1 or 2 then combination of annual MRI and
mammogram between ages 30-49yrs. Age 50-69
mammograms every 18 months then 3x/year after
69
Familial cancers
 High risk pedigrees
 Ovarian ca
 Only offered if FH includes either ovarian ca or the
person is a known BRAC carrier as part of UKFOCSS trial
which offers transvaginal ultrasound and regular ca 125
monitoring every 4 months
 CRC cancer
 People at high risk of hereditary non polyposis crc and crc
are offered 2 colonoscopies a year from ages 25-27 if they
have been assessed as a positive pedigree
Familial cancers
 Summary
 Family histories of cancer in primary care allows
GP’s to assess risk and make appropriate referrals.
 This allows families to benefit from relevant
targeted screening and gene testing as per
national guidelines.
Prenatal diagnosis
 Investigations include
 Chorionic villous sampling
 Amniocentesis
 Foetoscopy
 ultrasound
Prenatal diagnosis
 Tests offered
 Amniocentesis
 Karyotyping for chromosomal abnormalities
 Down’s syndrome
 X linked disorders
 Duchenne muscular dystrophy
 Gene probes to detect individual genes
 Cystic fibrosis
 Enzyme assay of cultured amniotic cells
 Inborn errors of metabolism
Prenatal diagnosis
 Risks of amniocentesis
 Singleton preg
0.5-1% foetal loss
 Multiple preg
3% risk foetal loss
 Foetal damage very rare
 Loss of one eye
 damage to brachial plexus
 Pneumothorax
 Lung hypoplasia
Prenatal diagnosis
 Tests offered
 Chorionic villus sampling
 Same tests as performed on amniocentesis
 Advantages
 Performed earlier in preg it top needed done at
much earlier stage before preg shows
 Results available quicker
Prenatal diagnosis
 Chorionic villus sampling
 Disadvantages
 Greater risk of foetal loss 3%
 Risk of foetal damage – limb agenesis due to
disruption of foetal blood vessels
 Chromosome analysis less accurate
 Result sometimes can’t be interpreted requiring
further tests
 Genetic mosiaicism between chorionic cells and the
foetus resulting in false positives and false negatives
i.e. Down’ syndrome
Prenatal diagnosis
 Foetoscopy
 Enables visualisation of foetus
 Foetal inspection – facial and limb abnormalities
 Foetal blood sampling – haemophilia, thalassaemia,
sickle cell, fragile X, alpha 1 antitrypsin deficiency
 Foetal skin biopsy – lethal epidermolysis bullosa
 Foetal liver biopsy – ornithine transcarbamylase
deficiency – loss = 5%
Diagnosis in genetic
counselling
 If a major chromosomal abnormality exists then a
recognised syndrome of 2 or more dysmorphic
features will usually be present chromosomal
analysis should be carried out if






Unexplained mental retardation
Known history of structural chromosomal problem
Unexplained stillbirth
Female with unexplained short stature
Recurrent miscarriages
Ambiguous sexual development
Ethical and legal
considerations
 Under congenital disabilities act 1976 an
action can be taken against anyone whose
negligent action resulted in a child being born
disabled, abnormal or unhealthy.
 It is the legal duty of all doctors to provide the
most recent valid information about genetic
disorders. If omitting to do so and on future
pregnancy a foetal abnormality occurred the
doctor would be liable to litigation
Genetics in Practice
 Neurofibrmatosis
 Sickle cell disease
 Beta thalssaemia trait
 Friedreichs ataxia
 Facial scapulo humeral dystrophy
 Beckers muscular dystrophy
Genetics in Practice
 Familial breast cancer – 3 families
 Fragile x