Добавлен: 10.02.2019
Просмотров: 11003
Скачиваний: 3
Chapter 7
Multifactorial Inherited Disorders
65
Example 7-2. Female-Biased Idiopathic Scoliosis
Idiopathic scoliosis is a lateral deviation of the vertebral column that involves both devia-
tions and rotation of the vertebral bodies due to unknown causes.
1.
If a female child in a family was born with idiopathic scoliosis, then the recurrence risk
to her future sister is 5.3%, whereas the recurrence risk to her future brother is 1.1%
However,
2.
If a male child in a family was born with idiopathic scoliosis, then the recurrence risk to
his future sister is 7.5%, whereas the recurrence risk to his future brother is 5.4%.
D. Degree of Relationship.
The recurrence risk in a multifactorial inherited disorder increases as
the closeness of the relationship to the proband increases
(crecurrence risk as ccloseness of
relationship)
.
For example, in cleft palate the recurrence risk is:
1.
4% for first-degree relatives
2.
0.7% for second-degree relatives
3.
0.3% for third-degree relatives which
equals the population incidence.
E. Number of Affected Relatives.
The recurrence risk in a multifactorial inherited disorder
increases as the number of affected relatives increases
(
↑
recurrence risk as
↑
number of
affected relatives)
.
This is because multiple affected relatives suggest a high liability in the
family for a multifactorial trait. For example, in cleft lip and cleft palate the recurrence risk is:
1.
4% after having one affected child
2.
10% after having two affected children
F. Severity of the Disorder.
The recurrence risk in a multifactorial inherited disorder increases as
the severity of the disorder increases
(crecurrence risk as cseverity of disorder)
.
This is
because a more severely affected individual suggests a high liability for the trait. For exam-
ple, in bilateral cleft lip and cleft palate the recurrence risk is:
1.
2.5% after having a child with unilateral cleft lip
2.
5.6% after having a child with bilateral cleft lip and cleft palate.
G. Consanguinity (kinship).
The recurrence risk in a multifactorial inherited disorder increases
as the consanguinity of the mating partners increases
(crecurrence risk as cconsanguinity).
This is because close consanguinity mating partners have high likelihood of sharing predis-
posing genes (i.e., a genetic relationship). For example, if the mating partners are first
cousins the risk of having a child with a birth defect is 6% to 10%. Whereas, the general pop-
ulation risk of having a child with a birth defect is 3% to 5%.
IV. SOME COMMON MULTIFACTORIAL CONDITIONS
A. Type 1 Diabetes.
1.
The characteristic dysfunction in this disorder is an
autoimmune destruction of pancreatic
beta cells
that produce insulin. This results clinically in hyperglycemia, ketoacidosis, and
exogenous insulin dependence.
2.
Type 1 diabetes demonstrates an association with the highly polymorphic
HLA (human
leukocyte antigen) class II genes,
which play a role in immune responsiveness and account
for
40% of familial clustering of Type 1diabetes. The specific loci involved in Type 1 dia-
betes are called
HLA-DR3
and
HLA-DR4 loci
located on
chromosome 6p
.
HLA-DR3 and HLA-
DR4 loci code for
MHC Class II cell-surface glycoproteins
that are expressed on antigen-
presenting cells (e.g., macrophages).
90% of Type 1 diabetic patients carry either the
HLA
DR3-DQ2 allele
or the
HLA DR4-DQ8 allele.
3.
It is hypothesized that alleles closely linked to HLA-DR3 and HLA-DR4 loci somehow alter
the immune response such that the individual has an immune response to an environ-
mental antigen (e.g., virus). The immune response “spills over” and leads to the destruction
LWBK274-C07_63-70.qxd 06/02/2009 03:49 PM Page 65 Aptara
of pancreatic beta cells. Markers for immune destruction of pancreatic beta cells include
autoantibodies to glutamic acid decarboxylase (GAD
65
), insulin,
and
tyrosine phosphatases
IA-2 and IA-2
.
At present, it is not known whether the autoantibodies play a causative role
in the destruction of the pancreatic beta cell, or whether the autoantibodies form second-
arily after the pancreatic beta cells have been destroyed.
4.
Clinical features include: neuropathy, retinopathy leading to blindness, and nephropathy
leading to kidney failure.
B. Type 2 Diabetes.
1.
Type 2 diabetes accounts for
90% of all cases of diabetes. In contrast to Type 1 diabetes,
there is almost always some insulin production. Type 2 diabetics develop insulin resist-
ance, a condition where the cells have reduced ability to use insulin.
2.
The disorder typically occurs in adults over 40 with the greatest risk factors being obesity
and a family history. Type 2 diabetes can usually be treated effectively by a combination of
diet modification and exercise. A regular exercise regimen can substantially reduce the
risk of developing the disorder, even in those with a family history. This is because regular
exercise helps prevent weight gain but it also aids in preventing the development of
insulin resistance.
3.
There is a strong genetic component to Type 2 diabetes because the concordance rate in
MZ twins is
90%. The recurrence risk for first-degree relatives is high (15%
→
40%).
Populations that have adopted Western diet and activity patterns show an increased inci-
dence of the disorder, most likely due to an increase in obesity.
4.
A number of genes have been linked to Type 2 diabetes but the genetic component of the
disorder is not completely understood.
C. Hypertension.
Hypertension is a major factor in cardiovascular disorder and strokes. The
heritability of hypertension is
20% to 40%. Although a number of genes have been linked to
hypertension, hypertension involves complex physiological processes that involve many
genes. The role of environmental factors is also recognized in the etiology of hypertension
(e.g., sodium in the diet, physical activity, and weight gain).
D. Heart Disease.
Some genes known to play a role in heart disease are involved with the regu-
lation of lipoproteins in the circulation. There are a number of risk factors for heart disease
(e.g., cigarette smoking, obesity, hypertension, high cholesterol, and a positive family his-
tory). The risk of developing heart disease increases in an individual who has:
1.
A first-degree affected male relative (recurrence risk
2 the general population risk)
2.
A first-degree affected female (least affected sex) relative (recurrence risk
2 the general
population risk)
3.
Many affected relatives (recurrence risk
2 the general population risk)
4.
Affected relative or relatives who were diagnosed with heart disease at
55 years of age
(recurrence risk
2 the general population risk)
E. Cancer (Table 7-1).
1.
Cancers are genetic disorders, but most of them are not strictly inherited. The fact that
cancers tend to cluster in families demonstrates that there is a genetic component to the
disorders as a group.
2.
For example, the risk of developing breast cancer doubles for first-degree relatives of
women diagnosed with the disorder. The risk also increases if more than one first-degree
relative has breast cancer and increases even more if the cancers developed relatively
early (before 45 years of age). However, the genetic components of many cancers are
poorly understood. The genes known to be involved in hereditary cancers will be dis-
cussed in Chapter 16.
3.
The role of environmental factors is also recognized in the etiology of many cancers (e.g.,
the role of tobacco use in lung cancer). The role of infectious agents is also recognized in
the etiology of
15% of cancers (e.g., the role of human papilloma virus [HPV] in cervical
cancer).
66
BRS Genetics
LWBK274-C07_63-70.qxd 06/02/2009 03:49 PM Page 66 Aptara
Chapter 7
Multifactorial Inherited Disorders
67
t a b l e
7-1
Environmental and Infectious Factors in Cancer
Factor
Cancer
Cigarette smoking (3-methylcholanthrene)
Squamous cell carcinoma of the lung
Asbestos
Pleural mesothelioma
Nitrosamines
Stomach carcinoma
Ultraviolet radiation
Melanoma, basal cell carcinoma, squamous carcinoma of the skin
Nulliparity
Breast cancer
Oral contraceptive
Estrogen replacement therapy
Low-fiber diet
Colorectal cancer
Nickel, silica, beryllium, chromium
Bronchogenic carcinoma
Benzene
Acute leukemia
Cyclophosphamide, ß-naphthylamine
Transitional cell carcinoma of the urinary bladder
Diethylstilbestrol
Clear cell carcinoma of the vagina
Human papilloma virus (HPV)
Carcinoma of the cervix
Human Herpesvirus 8 (HHV 8)
Kaposi sarcoma
Hepatitis B and C viruses (HBV and HCV)
Primary hepatocellular carcinoma
Human T-cell leukemia virus (HTLV-1)
T-cell leukemia and lymphoma
14
12
10
8
6
4
2
0
55
60
65
70
80
75
Number of men (thousands)
Height (inches)
Liability
Number of individuals
2 s.d. below
the mean
2 s.d. above
the mean
Mean
Unaffected
Affected
Threshold
A
B
FIGURE 7-1. Classes of multifactorial traits. (A) Quantitative trait.
This graphs shows height versus number of men in the
population. Note that this quantitative trait follows a normal distribution pattern in the population. (B) Threshold trait. This
graph shows liability versus number of individuals. Note the liability distribution where affected individuals (black area)
are seen only above the threshold. Unaffected individuals (light gray area).
LWBK274-C07_63-70.qxd 06/02/2009 03:49 PM Page 67 Aptara
68
1.
Recurrence risk for a multifactorially
inherited birth defect is higher in which of
the following circumstances?
(A)
the proband is of the less commonly
affected sex
(B)
the proband is less severely affected
(C)
only one person in the family is affected
(D)
the proband is a first cousin
2.
Which of the following best describes the
threshold of liability?
(A)
maximal risk for a trait with a bell-
shaped population distribution
(B)
a high discordance rate in dizygotic twin
pairs
(C)
a low concordance rate in monozygotic
twin pairs
(D)
minimal level of defect-causing genes
and environmental factors for trait
occurrence
Use the following pedigree for the next
question.
= clubfoot
Key
I
II
III
1
1
1
2
2
2
3
3
3
4
4
5
5
P
P
P
P
3.
Isolated clubfoot is more common in
males than females and follows multifactor-
ial inheritance. Who has the highest recur-
rence risk for clubfoot?
(A)
II-4
(B)
III-2
(C)
III-3
(D)
III-4
(E)
III-5
4.
In Ireland, the incidence of neural tube
defects is 1 in 200. What is the approximate
recurrence risk for first-degree relatives?
(A)
1 in 100
(B)
1 in 37
(C)
1 in 14
(D)
1 in 5
5.
A female child is born with pyloric steno-
sis, which is more common in males than in
females. Which of the following best
describes the recurrence risk to future
siblings?
(A)
The recurrence risk for a future brother
will increase.
(B)
The recurrence risk for a future sister will
increase.
(C)
The recurrence risk for both a future
brother and future sister will increase.
(D)
The recurrence risk for both a future
brother and future sister will not increase.
6.
Concordance for cleft palate is 25% for
monozygotic twins versus 10% for dizygotic
twins. Which of the following is indicated by
these figures?
(A)
Heritability for cleft palate is low.
(B)
There is a large genetic component to
cleft palate.
(C)
Heritability for cleft palate is high.
(D)
There is a small environmental compo-
nent to cleft palate.
LWBK274-C07_63-70.qxd 06/02/2009 03:49 PM Page 68 Aptara
7.
Which one of the following would be
expected to increase recurrence risk the
most for a multifactorial disorder?
(A)
The disorder occurs in a third-degree
relative.
(B)
There is one affected second cousin.
(C)
There is a first cousin with mild disease.
(D)
The parents are first cousins.
8.
A multifactorial disorder for which the
genetic component is thought to be involve-
ment of the HLA (human leukocyte antigen)
type II genes and the environmental compo-
nent is hypothesized to be infection with a
virus is which one of the following?
(A)
cancer
(B)
diabetes Type 1
(C)
diabetes Type 2
(D)
hypertension
9.
There are a number of risk factors in heart
disease, but the in the family history the
greatest risk would be due to which one of
the following?
Chapter 7
Multifactorial Inherited Disorders
69
(A)
having a maternal uncle with heart dis-
ease
(B)
having a paternal uncle with heart dis-
ease
(C)
having a mother with heart disease
(D)
having a father with heart disease
10.
Human papilloma virus is an infectious
environmental factor in which one of the fol-
lowing multifactorial diseases?
(A)
colorectal cancer
(B)
hepatocellular cancer
(C)
lung cancer
(D)
cervical cancer
11.
If the heritability (H) of a disorder is
entirely due to genetic factors, then H would
be equal to which one of the following?
(A)
0
(B)
0.01
(C)
0.10
(D)
1.0
LWBK274-C07_63-70.qxd 06/02/2009 03:49 PM Page 69 Aptara