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Genetic diseases

Disorders that have a


recognised genetic base

Main Categories of Genetic


Diseases

„ Single gene abnormalities

„ Chromosome abnormalities

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Single Gene Abnormalities
„ Due to a mutation involving a single gene
„ Mutant allele may be recessive or dominant
„ Found on the autosomal chromosomes or on
sex chromosomes
„ Heritable
„ Patterns of inheritance in a family can be
studied by using pedigree charts:
… Dominant traits - tend to occur in members of every generation
… Recessive traits - may remain hidden for generations before
showing itself
… Autosomal traits – occur in both males and females

… Sex inked traits- occur more in a particular sex

Genetic Diseases - Due to


Autosomal Dominant Inheritance
„ Disease expressed in homozygotes or
heterozygotes carrying the dominant allele
… need have only one abnormal allele of a gene

„ Either parent carrying the dominant allele can


pass the trait to their children
„ Both males and females affected the same
way
„ Eg: Huntingdon’s disease
… due to expression of an autosomal dominant
allele on chromosome 4

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Inheritance of autosomal Dominant
traits

In general, the following rules apply:


An affected person has an affected parent.
An affected person and an unaffected person have, on average, an
equal number of affected and unaffected children.
Males and females are equally likely to be affected
It is likely that each generation will have affected individuals

Genetic Diseases - Due to


Autosomal Recessive Inheritance
„ Due to genes present in autosomes in a
homozygous recessive condition
„ For an offspring to inherit the disease, both
the parents must be carriers (carry the gene)
„ Carriers are:
… Those who have the undesirable recessive allele in a
heterozygous state
… Phenotypically normal
… Capable of transmitting it to the next generation
„ Eg: Sickle cell anaemia, Albinism, Cystic
fibrosis

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Inherritance of Autosomal Recessive
traits

„ If normal parents have an affected child, both parents are


heterozygotes
„ If both parents are heterozygotes, 1/4 of their children will be
affected, 1/2 will be heterozygotes, and 1/4 will be normal.
„ All children of two affected persons will be affected.
„ All children of an affected person and a genotypically normal person will
be phenotypically normal heterozygotes.
„ Males and females are equally likely to be affected.

Genetic Diseases - Due to sex-


linked recessive inheritance
„ Diseases due to gene abnormalities in sex chromosomes
„ Most are due to genes located on the X chromosome (X-linked)
in a recessive condition
„ X-linked diseases - more likely to affect males than females
„ Females can act as carriers of the disease - if they carry one
recessive allele on the X chromosome (heterozygous for the
allele)
„ Patterns of inheritance of X-linked traits differ in the two
sexes because:
… in males: the genes on the X chromosome are expressed even though
they are in a recessive condition
… in females: expressed only if present on both X chromosomes –in the
homozygous recessive condition
„ Hence, chances of a female getting two X chromosomes that carry the
particular recessive allele are rare
„ Eg: Red-green colour blindness, Haemophilia

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Inherritance of X-linked
Recessive traits

„ Affected males transmit the trait to all of their daughters but not
their sons (male-to-male transmission does not occur).
„ Affected heterozygous females transmit the condition to 1/2 of
their children, regardless of sex.
„ Affected homozygous females transmit the trait to all of their
children.
„ Twice as many affected females as males will have the disorder

Chromosome Abnormalities
„ Due to deviations in chromosome number
„ Not heritable
„ Cause: due to non disjunction of chromosomes
during meiosis - failure of homologous
chromosomes to separate
… One daughter cell will receive both chromosomes of
one type while the other will receive no chromosomes
of that type
„ More likely to occur in the offspring of older
mothers
„ Chromosomes that fail to separate could be an
autosome or a sex chromosome

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Aneuploidy
„ Non-disjunction can occur with a single
pair of chromosomes
… Form gametes that have 2 chromosome of a
particular chromosome and the other having none
„ If a gamete with both pairs of a particular chromosome
fertilise with a more typical haploid gamete – form zygotes
with three chromosomes – Trisomic
„ If a gamete without any chromosomes of a particular type
fertilise with a more typical haploid gamete - a zygote with
only one chromosome - Monosomic

… Basic number of chromosomes is increased or


decreased in the zygote due to loss or addition of
one type of chromosome (2n +/- 1 chromosomes):
Aneuploidy

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Euploidy
„ Non-disjunction
can occur with
whole chromosome sets
…Form gametes that have one extra set
of haploid number of chromosomes
and others that have no chromosomes
…Basic number of chromosomes in the
zygote is increased or decreased by
the exact multiple of the haploid
number of chromosomes (2n +/- n) :
Euploidy

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Disorders due to Aneuploidy in
Autosomes

„ Down’s syndrome - mongolism


… 21st chromosome occurs in trisomy
… Occurs in about one in every 700 births
… Symptoms:
„ upwardly slanted eyes, epicanthal folds and protruding tongue.
„ Mental retardation
„ Short stature, stubby hands and feet
„ Sterile as their reproductive organs usually remain
underdeveloped
„ Usually die early

Disorders due to aneuploidy in sex


chromosomes
„ Turner’s syndrome
… XO condition - When an ovum lacking a X chromosomes is fertilised by
a normal sperm
… Have only 45 chromosomes
… Occur about 1 in 5000 births
… Symptoms
„ Female but breasts do not develop and sex organs are immature
„ Sterile
„ Short stature with webbed necks

„ Klinefelter’s syndrome
… XXY - When an ovum with two X chromosomes is fertilised by a normal
sperm
… Have a total of 47 chromosomes
… Occur in about 1 in 500 births.
… Symptoms
„ Male but has underdeveloped testes Sterile
„ Poorly developed secondary sexual characteristics
„ Partially developed breasts and somewhat feminine musculature

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Detection and treatment of
genetic abnormalities

„ Gene therapy
… Introducing a genetically engineered gene
to correct a copy of a defective gene

„ Genetic screening and counselling


… Before conception: by carrier recognition
… After conception: by prenatal testing
(foetal testing)

Carrier Recognition
„ Identifying persons carrying
alleles for a particular genetic
trait
„ May be identified by:
…Simple blood tests and other
chemical tests
…Sometimes even by DNA probes
…By pedigree charts to predict the
presence of a particular genetic trait

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Prenatal Testing
„ Amniocentesis:
… A needle inserted through abdominal
wall to withdraw a sample of amniotic
fluid
… Usually done between the 14th – 16th
week of pregnancy
… Foetal cells in the fluid are cultured
and karyotyped
… Takes about 4 weeks to give the result
… Risk to the foetus is low - about 0.5%

„ Chrorionic villi sampling:


… A needle inserted through the
cervix/abdomen removes a sample of
chorionic villi
… Usually done between 8-10 weeks o
pregnancy
… Villi cells are karyotyped – no
culturing necessary
… Results obtained with a day or two
… Risk to the foetus is more - about 2%

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