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Medical Genetics
多基因遗传疾病
Polygenetic disorders
Medical Genetics
Multifactorial inheritance is
responsible for the greatest number
of individuals that will need special
care or hospitalization because of
genetic diseases.
Medical Genetics
Up to 10% of newborn children will
express a multifactorial disease at some
time in their life.
Atopic reactions, diabetes, hypertension,
cancer, spina bifida/anencephaly, pyloric
stenosis, cleft lip, cleft palate, congenital
hip dysplasia, club foot, and a host of
other diseases all result from multifactorial
inheritance.
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The multifactorial model is
(1) Several, but not an unlimited number,
loci are involved in the expression of the
trait.
(2) There is no dominance or recessivity at
each of these loci.
(3) The loci act in concert in an additive
fashion, each adding or detracting a small
amount from the phenotype.
(4) The environment interacts with the
genotype to produce the final phenotype.
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Heritability
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The threshold model for multifactorial traits. Below the threshold the trait
is not expressed. Individuals above the threshold have the disease.
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Risk
(1) Recurrence risk increases with the number of
affected children in a family.
(2) Recurrence risk increases with severity of the
defect. A more severely affected parent is more
likely to produce an affected child.
(3) Consanguinity slightly increases the risk for an
affected child.
(4) If the two sexes have a different probability of
being affected, the least likely sex, if affected, is
the most likely sex to produce an affected
offspring.
Medical Genetics
1. schizophrenia , SP
Schizophrenia is a humorous
brain disorder characterized by
delusional thinking and unique but
unpopular perceptions.
Schizophrenia affects 1% of the
world population.
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Netherlandish painter: van gogh
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German musician :Robert Alexander Schumann
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Relationship Risk
Monozygotic twins 40-50%
Dizygotic twins 17%
Children 13%
Siblings 10%
Half siblings 6%
Grandchildren 5%
Nieces, Nephews 4%
Aunts, Uncles, Cousins 2%
General Population 1%
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Mental health professionals normally
diagnose this illness if, during any onemonth period of a person’s life, that
person has suffered two or more of the
following:
Delusions
Hallucinations
Disorganized speech
Grossly disorganized or catatonic behavior
Negative symptoms
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Negative symptoms are the most
insidious behavioral effects of
schizophrenia. They can include low levels
of:
Interest
Motivation
Emotional arousal
Mental activity
Social drive
Speech
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Schizophrenia is equally represented
in women and men. The onset of the
illness generally occurs at a later age in
women than in men (between ages 23 and
35 in women versus 18 to 25 for men).
Not only do women generally present with
schizophrenia at later ages, but the
phenomenon of late onset schizophrenia
(40+ years) is almost entirely a female
one.
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Subtypes of Schizophrenia
1. Disorganized Type
2. Catatonic Type
3. Paranoid Type
4. Undifferentiated Type
5. Residual Type
( waiting for psychiatry)
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Causes of schizophrenia
The cause of schizophrenia is
unknown. Many mental health
professionals believe there are
factors which increase an individual’s
risk of having schizophrenia.
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For example, first-degree
biological relatives of persons with
schizophrenia have a ten times
greater risk of developing the illness
than members of the general
population.
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Because there is no cure for
schizophrenia, the goal of treatment
is to eliminate or reduce symptoms,
minimize side effects, prevent
relapse, and socially and
occupationally rehabilitate the
patient.
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mental health professionals
generally begin advising their patients
of the schizophrenic likelihood of
suicide.
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Related genes——DRD genes
DRD3 gene
dopamine receptor D3, located on 3q13.3
normal function of the DRD3 gene
The DRD3 gene provides instructions for
making a protein called dopamine receptor D3,
which is found in the brain. This protein responds
to the chemical messenger (neurotransmitter)
dopamine to trigger signals within the nervous
system, including signals involved in producing
physical movement.
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• excitatory neurotransmitter
• DRD3 expressed in endbrain、
hippocampi（Emotional arousal
Mental activity ）
• antagonist of DRD3 receptor
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DRD2 gene (11q22.1-11.3)
141c missing
DRD4 gene (11q15.5)
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5-HTR2A（13q14）
• 5-HTR：inhibitory transmitter
• agonist
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• KCNN3 gene (1q21.3)
K+ channel of cell membrane
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• MTHFR\RGS4\CH13L1\DISC1\ERBB4
\SYN2\PMX2B\EPNR\DTNBP\NOTCH4
\TRAR4\NRG1\GRIN1\BDNF\FYXD6\
DAO\NOS1\G72\AKT1\CHRNA7\SLC6
A4\SLC6A4\GNAL\C3\APOE\COMT\Z
DHHC8\PRODH\RTN4R
Medical Genetics
2. diabetes mellitus
The term diabetes mellitus
describes a metabolic disorder of
multiple aetiology characterized by
chronic hyperglycaemia with
disturbances of carbohydrate, fat
and protein metabolism resulting
from defects in insulin secretion,
insulin action, or both.
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Symptoms： such as thirst, polyuria,
blurring of vision, and weight loss.
In its most severe forms:
ketoacidosis ,state may develop and
lead to stupor, coma and, in absence
of effective treatment, complication，
death.
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risk：
• potential blindness
• foot ulcers, features of autonomic
dysfunction, including sexual
dysfunction.
• cardiovascular, peripheral vascular
and cerebrovascular disease.
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Aetiological Classification of Disorders
of Glycaemia
Type 1 : (beta-cell destruction,
usually leading to absolute insulin
deficiency)
• Type 2 : (may range from
predominantly insulin resistance with
relative insulin deficiency to a
predominantly secretory defect with
or without insulin resistance)
• Gestational diabetes
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Diagnosis ：Blood sugar, urine sugar
Treatment: food control (starch
fructose？)
medicine （Glucobay）
insulin injection
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Genetic defects
Several forms of the diabetic state may
be associated with monogenic defects in
beta-cell function, frequently characterized
by onset of mild hyperglycaemia at an
early age (generally before age 25 years).
They are usually inherited in an
autosomal dominant pattern. Patients with
these forms of diabetes, have impaired
insulin secretion with minimal or no defect
in insulin action .
Medical Genetics
Abnormalities at several genetic
loci on different chromosomes have
now been characterized.
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HNF1alpha（hepatocyte nuclear factor）
The most common form is
associated with mutations on
chromosome 12 in a hepatic nuclear
transcription factor referred to as
HNF1alpha .
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HNF1alpha is a key transcription factor
that is essential for pancreatic betacell development and function
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glucokinase gene
A second form is associated with
mutations in the glucokinase gene on
chromosome 7p.
Glucokinase converts glucose to
glucose-6-phosphate, the
metabolism of which in turn
stimulates insulin secretion by the
beta cell.
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Thus, glucokinase serves as the
"glucose sensor" for the beta cell.
Because of defects in the glucokinase
gene, increased levels of glucose are
necessary to elicit normal levels of
insulin secretion.
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HNF4alpha gene
A third form is associated with a
mutation in the HNF4alpha gene on
chromosome 20q . HNF4alpha is a
transcription factor which is involved
in the regulation of the expression of
HNF1alpha.
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IPF-1
A fourth variant has recently been
ascribed to mutations in another
transcription factor gene, IPF-1,
which form leads to total pancreatic
agenesis . 13q12.1
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Point mutations in
mitochondrial DNA have been found
to be associated with diabetes
mellitus.
The most common mutation
occurs at position 3243 in the tRNA
leucine gene, leading to an A to G
substitution.
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Environmental factors:
• Fat
• Pregnant
• Unhealthy food
• Without exercise
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3. bronchial asthma
Bronchial asthma, including
shortness of breath and wheezing (a
whistling sound in the chest).
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For most people with bronchial
asthma, the pattern is periodic
attacks of wheezing alternating
with periods of quite normal
breathing. However, some people
with bronchial asthma alternate
between chronic shortness of breath
and episodes of even worse
shortness of breath.
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The symptoms of bronchial asthma
include:
• a feeling of tightness in the chest;
• difficulty in breathing or shortness of
breath;
• wheezing;
• coughing (particularly at night).
Medical Genetics
Asthma is found in 3-5% of
adults and 7-10% of children. Half of
the people with asthma develop it
before age 10, and most develop it
before age 30. Asthma symptoms
can decrease over time, especially in
children.
Medical Genetics
Strong risks for developing
bronchial asthma include being a
person who is genetically susceptible
to asthma and being exposed early
in life to indoor allergens, such as
dust mites and cockroaches, and
having a family history of asthma or
allergy.
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• Indoor allergens, such as dust mites
and cockroaches,
• Outdoor allergens such as pollen
• Food such as seafood, peanut
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Bronchial asthma attacks can be
triggered (precipitated or aggravated) by
various factors, including:
respiratory tract infections;
cold weather;
exercise;
cigarette smoke and other air pollutants;
stress.
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In sensitive individuals, asthma
symptoms can be triggered by inhaled
allergens (allergy triggers), such as pet
dander, dust mites, cockroach allergens,
molds, or pollens. Asthma symptoms can
also be triggered by respiratory infections,
exercise, cold air, tobacco smoke and
other pollutants, stress, food, or drug
allergies.
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Gene-environment interactions in
the early life origins of asthma
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Genetic and Molecular Regulation of
ADAM33
ADAM33 was the first asthma
susceptibility gene identified as a result of
a genome-wide positional cloning effort.
The identification of ADAM33 as a major
risk factor involved in the pathogenesis of
bronchial hyper-responsiveness (BHR) and
airway wall remodeling.
ADAM33, which causes the bronchiole
smooth muscles to be hypersensitive.
Medical Genetics
• PHF11, comes from chromosome 13
The gene appears to regulate the
blood B cells that produce
Immunoglobulin E, the allergic
antibody
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• TCQ2（14q11.12）
T cell receptor，can regulate the
reaction of IGgE
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• ADRB3
Beta-adnephrin receptor，related
with airway reactivity
One such gene would be TGFB1 which
plays an important role in control of
expression of antibodies.
Medical Genetics
• KCNS3
• HNMT
• MUC7
• ILI3\ILI2B
• SCGB342
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