MOLECULAR AND GENETIC MEDICINE
Lec:2
Dr.Mohammed Alhamdany
Patterns of disease inheritance
Autosomal dominant inheritance
Autosomal dominant disorders are caused by inheritance of a
genetic abnormality in only one of the two copies (alleles) of a
single gene. The risk of an affected individual transmitting an
autosomal disease to his or her offspring is 50% for each
pregnancy, since half the affected individual gametes (sperm or
egg cells) will contain the affected chromosome and half will
contain the normal chromosome. However, even within a
family, individuals with the same mutation rarely have identical
patterns of disease due to variable penetrance and/or
expressivity. Penetrance is defined as the proportion of
individuals bearing a mutated allele who develop the disease
phenotype. The mutation is said to be fully penetrant if all
individuals who inherit a mutation develop the disease.
Expression is the variation of disease severity for the same
genotype. Neurofibromatosis type 1 is an example of a disease
that is fully (100%) penetrant but which shows extremely
variable expressivity.
Autosomal recessive inheritance
In autosomal recessive disorders, both alleles of a gene must be
mutated before the disease is manifest in an individual, and an
affected individual must inherit one mutant allele from each
parent. The distinguishing feature of recessive diseases is that
carrying one mutant allele does not produce a phenotype
(carrier). Autosomal recessive disorders are rare in most
populations. For example, the most common serious autosomal
recessive disorder in the UK is cystic fibrosis, which has a birth
incidence of 1:2500.
Genetic risk calculation for a fully penetrant autosomal
recessive disorder is straightforward. Each subsequent
pregnancy of a couple who have had a previous child affected
by an autosomal recessive disorder will have a 25% (1:4) risk of
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being affected; a healthy individual who has a sibling with an
autosomal recessive disorder will have 2/3 chance of being a
carrier.(why? Please look to the figure in the last of the lecture)
X-linked inheritance
Genetic diseases caused by mutations on the X chromosome
have specific characteristics. X-linked diseases are mostly
recessive and restricted to males who carry the mutant allele.
This is because males have only one X chromosome, whereas
females have two. Thus females who carry a single mutant allele
are generally unaffected. Occasionally, female carriers may
exhibit signs of an X-linked disease due to a phenomenon called
skewed X-inactivation. All females will inactivate one of their
two X chromosomes in each cell at a point during development.
This process is random in each cell but if, by chance, there is a
disproportionate inactivation of normal X chromosomes
carrying the normal allele, then an affected female carrier will
be more likely. X-linked recessive disorders have a recognisable
pattern of inheritance, with transmission of the disease from
carrier females to affected males and absence of father-to son
transmission. The risk of a female carrier having an affected
child is 25% (1:4; half her male offspring).
Q: write the conditions in which the female can affected by X
linked recessive genetic disorder? ( 3 )
Mitochondrial inheritance
The inheritance of mtDNA disorders is characterised by
transmission from females, but males and females are generally
equally affected. Unlike all the other inheritance patterns
mentioned above, mitochondrial inheritance has nothing to do
with meiosis but reflects the fact that mitochondrial DNA is
transmitted by oöcytes. Mitochondrial disorders tend to be very
variable in penetrance and expressivity within families.
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Classes of genetic variant
There are many different classes of variation in the human
genome . Rare genetic variations which result in a disease are
generally referred to as mutations, whereas common variations
and those which do not cause disease are referred to as
polymorphisms. These different types of variation are further
categorised by the size of the DNA segment involved and/or by
the mechanism giving rise to the variation. it include:
1-Nucleotide substitutions
The substitution of one nucleotide for another is the most
common type of variation in the human genome. Depending on
their frequency and functional consequences, these changes are
known as a point mutation or a single nucleotide polymorphism.
When these substitutions occur within ORFs of a protein-coding
gene, they are further classified into:
• synonymous (resulting in a change in the codon but no change
in the amino acid and thus no phenotype)
• missense (altering a codon, resulting in an amino acid change
in the protein)
• nonsense (introducing a premature stop codon, resulting in
truncation of the protein).
2-Insertions and deletions
One or more nucleotides may be inserted or lost in a DNA
sequence, resulting in an insertion/deletion (in-del)
polymorphism or mutation . If an indel change affects one or
two nucleotides within the ORF of a protein- coding gene, this
can have serious consequences because the triple nucleotide
sequence of the codons is disrupted, resulting in a frameshift
mutation. The effect upon the gene is typically severe because
the amino acid sequence is totally disrupted.
3-Simple tandem repeat mutation
Variations in the length of simple tandem repeats of DNA are
thought to arise as the result of slippage of DNA during meiosis
and are termed microsatellite (small) or minisatellite (larger)
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repeats. These repeats are unstable and can expand or contract in
different generations. This instability is related to the size of the
original repeat, many doesn't had effect ,However, some genetic
diseases, including Huntington disease and myotonic dystrophy,
are caused by microsatellite repeats which result in duplication
of amino acids .
4-Copy number variations
Variation in the number of copies of an individual segment of
the genome from the usual diploid (two copies) content can be
categorised by the size of the segment involved. Rarely,
individuals may gain or lose a whole chromosome. Such
numerical chromosome anomalies most commonly occur by a
process known as meiotic non-dysjunction . This is the most
common cause of Down’s syndrome, known as trisomy (three
copies) of chromosome 21.
Examples of chromosome and contiguous
disorders:
1-Numerical chromosomal abnormalities
gene
Down’s syndrome (trisomy 21) 47,XY,+21 :,Characteristic facies,
IQ usually < 50, congenital heart disease
Klinefelter’s syndrome 47,XXY :Phenotypic male, infertility,
gynaecomastia, small testes
Turner’s syndrome 45,X :Phenotypic female, short stature, webbed
neck, coarctation of the aorta, primary amenorrhoea
2-Recurrent deletions, microdeletions
Di George/velocardiofacial syndrome :Cardiac outflow tract
defects, distinctive facial appearance, thymic hypoplasia, cleft
palate and hypocalcaemia.
3-Diseases associated with triplet and other repeat
sequences
Coding repeat expansion: Huntington disease
Non-coding repeat expansion: Myotonic dystrophy, Friedreich’s
ataxia.
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General principles of diagnosis of genetic disease:
1- Clinical history and examination, routine Ix, for patient and his family.
2-Constructing a family tree: include detail about 3 generations.
3-Polymerase chain reaction (PCR) and DNA sequencing: Almost any
tissue can be used to extract DNA for PCR analysis, but most commonly,
a sample of peripheral blood is used.
4-Assessing DNA copy number: Visible microscopy for detecting
the gain or loss of whole chromosomes or large chromosomal segments
(> 4 million bp). Detection of submicroscopic chromosome anomalies
requires special techniques for identification . Fluorescent in situ
hybridisation (FISH) and multiplex ligation-dependent probe
amplification (MLPA) are two of the most widely used techniques to
identify such syndromes. However, the availability of whole-genome
microarrays has revolutionised chromosome analysis, as it allows the
rapid detection of gain or loss of any segment of DNA throughout the
genome.
5-Non-DNA-based methods of assessment: Although DNAbased diagnostic tools are used in the vast majority of patients with
suspected genetic disease, it may sometimes be more economical or
convenient to measure enzyme activity rather than sequencing the coding
region of the genes involved.
Genetic testing in pregnancy
Methods used in prenatal testing
1-Ultrasound: in 1st trimester onwards as increased nuchal translucency
(an edematous flap of skin at the base of the neck) for trisomies and
Turner’s; all major abnormalities such as neural tubal defect, congenital
heart disease.
2-Chorionic villus biopsy: From 11 weeks complicated by 2% risk of
miscarriage; it used for early chromosomal, DNA and biochemical
analysis.
3-Amniocentesis: From 14 weeks complicated by < 1% risk of
miscarriage; it used for chromosomal and some biochemical analysis, e.g.
alpha-fetoprotein for NTD.
4-Cordocentesis: From 19 weeks complicated by 2–3% risk of
miscarriage; a highly specialised test; used for chromosomal and DNA
analysis.
Indication of prenatal test:
1-Advanced maternal age and a high-risk serum screening
result.
2- A previous child with a detectable chromosome abnormality.
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3- A parent or child with a genetic disease for which testing is
available.
4-Abnormal antenatal scan
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