Download Genetics Genetics Disorders

Genetics
Nsg 3027
Women’s Health
Introduction
• Genetic disorders occur
approximately 1 in 20 or
30% of pediatric
admissions
National Health Care
Goals:
Increase prenatal screening
to 90% of pregnancies.
Increase state sponsored
programs to cover at least
95% of newborns, having
positive tests, receive
appropriate care.
Genetics Disorders
• Defined as diseases that can be passed
down from one generation to the next.
• Some are so severe, the fetus cannot
survive.
• Others are only apparent with testing.
• Some come with extensive family
histories, and some reveal no family
history.
1
OBJ 1: Describe the basic unit of
inheritance
• Genes are the basic unit of heredity, and
are made of DNA. Genes are responsible
for an individual’s physical and cognitive
characteristics such as hair and eye color.
• Chromosomes are the woven strands of
DNA which are contained in the nucleus of
each body cell. On the chromosomes lay
the genes in orderly sequences.
Chromosomes and genes
2
OBJ 2 : Write the number of
chromosomes in body cells and
reproductive cells
Each body cell contains 46 chromosomes,
except for the reproductive cells ( sperm
and ova). The reproductive cells only
contain 23 chromosomes.
• Somatic or body cells = 46 chromosomes
• Reproductive cells = 23 chromosomes
Number of Chromosomes
• Somatic cell chromosomes exist in pairs.
The two will actually look alike.
• So every somatic cell contains 22 pairs
and 2 sex chromosomes, not 23 pairs because the reproductive cells ( Sperm
and Ova) are not necessarily in pairs
• Body cells or Somatic cells =
22 pairs + 2 sex chromosomes
3
Chromosome Arm Structures
• Chromosomes are structured with 4
“arms” in the two matched pair of
chromosomes.
• The arms are joined at the center – point
called a “centromere”.
3 Arm Structures
• There are 3 kinds of arm structures:
Metrocentric – centromere is located in the
middle making all 4 arms equal.
Submetrocentric - centromere is located
below center resulting in 2 long upper
arms.
Acrocentric – centromere is located above
center resulting in 2 short upper arms
4
Sex Chromosomes
• Reproductive cells (ova and sperm) have
only 23 chromosomes each.
• When conception occurs, the new
individual has 23 chromosomes from the
sperm and 23 chromosomes from the ova,
making a total of 46 chromosomes for the
new individual.
• 23 (sperm) + 23 (ova)= new individual (46)
How do scientist know all this?
OBJ 3: Explain the process of sex
determination
There are 2 kinds of sex chromosomes:
X and Y
All ova have one X chromosome.
Sperm have either one X or one Y
chromosome in each little wriggly fellow.
When the sperm and ova combine at
conception, sex is determined.
If 2 X’s are combined, a female results (XX)
If an X and a Y combine, a male results (XY)
5
OBJ 4: Define alleles and their role in
expression of genetic traits
• Every somatic cell has 22 matched
chromosomes and 2 sex chromosomes except for the reproductive cells.
• On each matched chromosome, the genes
are arranged in the same order on each
chromosome.
Example of alleles in expression of
genetic traits
• For example, the genes for eye color are
located in the same place on each
matching chromosome. Each individual’s
eye color depends on 2 genes-- one gene
on each of the matching chromosomes.
The genes combine to determine how a
given trait will be expressed. The two
genes for the same trait are called alleles.
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Matching chromosomes
OBJ 5 : Explain dominant and
recessive genes
• A pair of genes or alleles are combined at
conception.
• If a gene is dominant, that means its
characteristics will be expressed over any
other allele.
• If a gene is recessive, that means the
gene will not be expressed over the other
allele for that trait.
7
OBJ 6 : Define homozygous and
heterozygous
• The two paired genes or alleles can also
be described as :
• Homozygous – the alleles are alike
Eg. 2 recessive genes for a trait are
homozygous.
Heterozygous – the alleles are different
Eg. 1 recessive and 1 dominant gene
would be heterozygous.
Homozygous vs Heterozygous
Review #1- Match the following
•
•
•
•
•
•
1.______ Genes
2.______ Chromosomes
3.______ Metrocentric
4.______Submetrocentric
5.______ Acrocentric
Match these words with the choices in the
next slide. There is 1 extra choice
8
Matching choices
• A. Strands of woven DNA
• B. Centromere is located below the center
making 2 long upper arms, and 2 short.
• C. Chromosomes are structured with 4
arms
• D. Responsible for an individual’s physical
characteristics
• E. Centromere is located in the center of
the chromosomes making 4 equal length
arms
• F. Centromere is located so there are 2
short upper arms, and 2 long lower arms.
Review #2 - Using the previous slide, tell the
numbers of the chromosomes in the karyotype
which meet the following description:
• Example : #1 is metrocentric, so list #1 by
Metrocentric.
• Acrocentric
• Metrocentric
• Submetrocentric
9
OBJ 7: Define genome and apply to a
normal male and female
Genome is the actual genetic composition of
an individual. It can be expressed as
follows:
• 46XX which would describe normal
female
• 46XY would describe a normal male
• In other words, the female has 46 total
number of chromosomes and 2 “ X “ sex
chromosomes, and the male 46 total
chromosomes with an “X” and a “ Y”
OBJ 8: Define phenotype and give an
example of how it is used
• Phenotype refers to the outward
appearance of an individual.
• In other words, “how they appear” – looks
like a male or female. Has apparent
sexual characteristics like a male or
female. Is short – tall - slanted eyeslarge hands, etc.
• Example: “He has the phenotype of a
male. “
OBJ 9: Define genotype and karyotype
• Genotype refers to the actual genetic
composition of an individual
• Karyotype refers to the display of the
number, size and shapes of the
chromosomes of a representative body
cell.
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Karyotyping
Review # 3 - Match the terms on this slide
with the definitions on the next slide
•
•
•
•
•
•
1.______
2.______
3.______
4.______
5.______
6.______
Genome for a normal male
Phenotype
Genotype
Karyotype
Homozygous
Heterozygous
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•
•
•
•
•
•
•
Match these definitions to the terms in the
previous slide
A. Presentation of the number, size , and
shape of a complete set of chromosomes.
B. 2 matching alleles.
C. Outward appearance of an individual.
D. A pair of matching chromosomes.
E. Refers to the actual genetic
composition of an individual.
F. Alleles that are not alike.
G. 46XY
OBJ 10 : Define the terms describing
chromosomal abnormalities
• Deformities of chromosomes are
designated by the following symbols:
• p = short arm defect
• q = long arm defect
• + = an added chromosome
• - = a missing chromosome
Genomes for Chromosomal
Abnormalities
• Write the defect after the sex chromosome
designation in a genome as follows:
• A female with a missing short arm on
chromosome 5 would be 46XX5p• A male with an added chromosome at
chromosome 21 would be 47XY21+
• A female with a long arm added on
chromosome14 would be 47XX14q+
12
Review #4 Match the following defects with their
genome: (Each defect can have more than one answer)
•
•
•
•
1. ______
2. ______
3. ______
4. ______
Short arm defect
Long arm defect
One extra chromosome
A missing chromosome
• A. 46XY5p• B. 47XX13+
• C. 45XY22q-
D. 45XX0
E. 47XX5pF. 47XY21
Chromosomal Disorders
Patterns of
Inheritance
13
Mendelian Inheritance
• Mendelian Inheritance is a pattern which
can predict the inheritance of physical
characteristics of individuals. It follows a
set of orderly rules of inheritance.
OBJ 11: Describe the inheritance pattern of
Autosomal Dominant pattern and why it is
the least prevalent of the disorders
• These disorders usually affect major body
systems and have a grave or fatal
prognosis. Thankfully, this makes the
dominant pattern the least prevalent.
Autosomal Dominant Disorders
• The disease is expressed in every
individual with 1 affected allele. There are
no carriers
• Vertical transmission pattern- 1 of the
parents of a diseased child will have the
disease.
• The sex of an affected individual is
unimportant in terms of the inheritance.
• There is usually a history of the disease in
other members of the family.
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Autosomal Dominant Disorders
• Example: Huntington’s disease. Result of
a dominant diseased gene on
chromosome 4. It is a neurologic disorder
which is progressive and fatal. There is no
cure.
Autosomal Dominant Disorders
Autosomal Dominant Disorders
15
OBJ 12 : Describe the family history and the
composition of alleles that make-up the
Autosomal Recessive Disorders
• This is the most prevalent type of
Mendelian inherited diseases. It usually
involves enzyme or biochemical
deficiencies, and can be treated.
• An individual must have 2 recessive
alleles together to manifest the disease.
• Both parents of the child with the disorder
are clinically free of the disease, but are
carriers.
Autosomal Recessive Disorders
• The sex of the diseased individual is
unimportant in the inheritance pattern.
• Horizontal transmission pattern- there is
no reported history of the disease in either
of the parent’s families.
• If parents are heterozygous (only possess
one of the diseased alleles) they will not
manifest the disease, making no family
history of the disorder. However, they will
be carriers.
Autosomal Recessive
• Example : Cystic Fibrosis is caused by a
gene on the 7th chromosomes. As many
as 1 in 29 Caucasians carry the trait. DNA
analysis would reveal the recessive trait
and help the parents make a more
informed reproductive choice.
16
OBJ 12 : List 5 Autosomal Recessive Disorders
and explain how the diseases are inherited,
noting the frequency of inheritance of disorders in
subsequent pregnancies.
• Other Examples are PKU, Tay-Sachs
disease, Sickle cell anemia, and Rh
Incompatibility.
• The inheritance pattern is the same for
every pregnancy. In other words , the
genes do not mark off the odds on a score
card and keep track of what happened
with each pregnancy. This is true of all
inheritance patterns.
Autosomal Recessive inheritance
pattern
• If both parents are heterozygous ( possess
only 1 diseased gene each), they will
have no disease, but will be carriers. In
this situation, there would be no family
history upon assessment.
• Their offspring will have a 1 in 4 chance
(25%)of having the disease. They will
have 1 in 2 (50%) will be carriers. And 1
child will be healthy. Example follows…..
17
Review #5 - Tell the number of children who
will be diseased in the following scenario for
an autosomal dominant disease
• 1. A father is healthy
and the mother is
heterozygous for an
autosomal dominant
disease. What are
the chances of them
having a diseased
offspring?
• D= Diseased gene
• h= Healthy gene
D
h
h
h
Review #5 continued
• 2. Both the mother and
father are heterozygous for
PKU. What kind of
transmission pattern is
involved with PKU? What
is the chance of these
parents having a diseased
child?
• h = Healthy
• D = Diseased
h
D
h
D
Review #5 cont’d
• 3. If the parents in Question #2 have their
first pregnancy yielding a healthy child,
what is the chance of their having a
healthy child in their second pregnancy?
• 4. Why are autosomal recessive diseases
more prevalent than the autosomal
dominant diseases?
• 5. Could a couple who has no history of
autosomal recessive disease in either of
their families benefit from genetic
counseling? Why?
18
Review #5 cont’d
6. In this scenario for an Autosomal
recessive disorder, answer the following:
Number of female offspring:
Normal?
Carriers?
Diseased?
Number of male offspring:
Normal?
Carriers?
Diseased?
Review #5
• 7. What are 5 autosomal recessive
diseases?
X Linked Diseases
also called sex-linked diseases
19
OBJ13 :Explain the inheritance pattern
for both male and female offspring with
X Linked Recessive Disorders
• Example : Hemophilia A - is a clotting factor
VIII deficiency. ie. does not make
thromboplastin. Incident is 1 in 10,000 males.
• Only males in the family have the disorder.
If they inherit a diseased X from the mother, they
will be diseased. The Y chromosome when
paired with the diseased X, does not carry
enough genetic material to cancel out the
diseased gene. So, the male offspring is
diseased.
X Linked Recessive Disorders
• Females who are heterozygous ( with one
X diseased, the other X is healthy) do not
have the disease, but are carriers. The
genetic material on the other healthy X is
enough to cancel out the disease.
• Females who are homozygous ( have 2
diseased X ‘s) will abort spontaneously
before term.
• Mothers who are heterozygous will not be
diseased, but can pass the diseased X to
the son, who will be diseased.
X-Linked recessive disorders
The Dorque Family
20
X-Linked Recessive disorders
Mrs. Dorque’s sister’s family
X-Linked Recessive Disorder with the
father healthy and the mother
heterozygous ( slide 62 )
21
Review #6
• 1. In the scenario where the father is
healthy and the mother is heterozygous,
what is the chance of the couple having a
healthy female, a healthy male, a healthy
child of any sex?( refer to slide #62)
• 2. In the scenario that a female offspring
is homozygous for the diseased X, what
would be the outcome? Diseased or
Healthy?
Review # 6 cont’d
• 3. Why is a heterozygous female a carrier, but a
heterozygous male is diseased in recessive sex
linked inheritance ?
• 4. Is there always a family history of genetic
disorders when a recessive x-linked disorder is
expressed in an offspring? Give an example?
• 5. In the following scenario : a couple has a
healthy father and a heterozygous mother for a
recessive X-linked disorder, what percentage of
male children would be healthy? Diseased ?
Refer to slide #62.
6. Tell the frequency of affected children when
both parents are heterozygous for an X-linked
recessive disease.
Number of female:
Normal?
Carriers?
Diseased?
Number of male :
Normal?
Carriers?
Diseased?
22
OBJ 14: Describe the genetic inheritance pattern
for X-Linked Dominant Disorders and determine
the frequency of disease expression in both male
and female offspring in different scenarios
• A gene for these disorders is located on
the X sex chromosome. Because the gene
is dominant, only one X chromosome with
the diseased gene will cause the individual
to have the disease. If the gene is present,
the individual will be diseased.
• All individuals – male or female - will be
diseased if they have 1 affected gene.
There are no carriers.
X-Linked Dominant Disorders
• The male offspring of an affected dad will
not be affected, but 50% are affected from
a heterozygous mother.
• The female offspring are affected by
either a diseased mom or dad.
• All children of a homozygous mother are
affected. 50% of all children from a
heterozygous women are affected.
• In the family history, the dominant disorder
appears in every generation.
X-Linked Dominant Disorders
• Example : Alport’s syndrome
• It is a disease of progressive kidney
failure, and most do not live to reproduce –
making the disease rare.
• This is the case with dominant X- linked
disorders – they are usually more severe
but less prevalent.
• There is frequently family history of the
disorder to report.
23
Frequency of Inheritance
• A father who is heterozygous ( having 1 affected
X) for a dominant x-linked disorder, will be
diseased. If he has a daughter with a healthy
mother, the girls will be diseased. If he has a
male with a healthy mother, the sons will be
healthy.
• If a father who is disease free has offspring with
a heterozygous mom, 50% or 1 in 2 of the
daughters will be diseased. And 50% or 1 in 2 of
the sons will be diseased .
Review #7
1. Number of female:
Normal?
Carriers?
Diseased?
Number of male :
Normal?
Carriers?
Diseased?
Review #7
2. Number of female:
Normal?
Carriers?
Diseased?
Number of male :
Normal?
Carriers?
Diseased?
24
Review #7
X-Linked Dominant
Xa =Healthy XA = Diseased
3. Number of females:
Normal?
Carriers?
Diseased?
Number of males :
Normal?
Carriers?
Diseased?
OBJ 15 : Explain the difference
between Mendelian inherited diseases
and Multifactoral diseases
• Multifactoral Inheritance
• Do not follow Mendelian laws. Multifactoral
diseases are caused by defects in
multiple genes. These diseases may also
be affected by environmental factors.
• Example is Diabetes Mellitus. The disease
is affected by the unhealthy eating
patterns in a family. The eventual weight
gain results in the onset or worsening of
the disease.
OBJ 16 : Explain how Mitochondrial
Inheritance Imprinting can be used to
track genetic traits
• Mitochondria from the ova, may be passed
on to the offspring. Because the
mitochondria can only be from the mother,
they serve as markers for genes which are
maternal in origin. Mitochondria can be
detected in genetic tests to determine if a
gene is passed on by the mother.
• Imprinting allows us to determine if a
genetic disorder comes from the mother or
father
25
Review #7 : Match each of the inheritance patterns
with its unique characteristics ( Each choice may
have more than 1 answer)
•
•
•
•
6. ______Autosomal dominant
7. ______Autosomal recessive
8. ______X-linked dominant
9. ______X-linked recessive
• See next slide for matching definitions!
Matches for terms listed on previous
slide
• A. Only 1 allele has to be present to have the
disease to have the disease in a male or female.
• B. 2 alleles alike must be present to manifest
the disease.
• C. The disease cannot be passed from a father
to a male child.
• D. A female child who inherits one diseased
allele from her father and one healthy allele from
her mother will not be diseased
Cytogenic Disorders
Disorders caused by a fault in the
number or structure of
chromosomes
26
OBJ 17 : Explain the mechanism which
created Nondisjunction abnormality
such as Down’s syndrome or Trisomy’s
• Uneven cell division in meiosis causes a
new reproductive cell to have 22 or 24
chromosomes instead of 23. When this
cell combines with another reproductive
cell at conception, the new individual has
45 or 47 chromosomes instead of 46.
• “Non Disjoining “ for memory purposes i.e.
doesn’t separate correctly.
Nondisjunction abnormalities
• Most fetuses with only 45 chromosomes
will not live to term. Exception is Turner’s
syndrome!
• However, 47 chromosomes allows for
adequate genetic information, but creates
abnormalities such as Trisomy 21.
Mechanism of Nondisjunction
27
OBJ 16 : Give examples of
Nondisjunction Abnormalities
explaining the defective chromosomes
and phenotypes
• Down’s syndrome – Female with Downs
would be 47XX21+. There is also a
trisomy at chromosome 13 or 18
• Usually associated with maternal age >35
or paternal age >55, which points to the
likelihood of uneven meiosis( reproductive
cell division ) in the older parents being
less efficient.
Trisomy 18
Trisomy 21
28
Down’s Phenotype
Other examples of Nondisjunction
• Turner’s syndrome – 45 XO. The O is a
defective X chromosome. Female
phenotype with poorly developed genitalia
and are usually sterile. Other
characteristics include: short stature,
webbed neck, and possible cognitive
impairment
• Klinefelter’s syndrome 47XXY. Male
phenotype with gynecomastia,
underdeveloped male genitalia, and
possible cognitive impairment
Nondisjunction Karyotypes
29
Turner’s syndrome
Klinefelter’s syndrome
OBJ 17 : Explain the difference
between Nondisjunction and Deletion
Abnormalities
Deletion Abnormalities are a
Form of disorder in which a part of a
chromosome breaks off in cell division
causing a new individual to be plus or
minus a portion of a chromosome.
• Example: Cri-du-chat also called Cat’s cry
syndrome. The male would have the
genome : 46XY5q-
30
Cri-du-chat / 46XY5p-
Phenotype of Cri-du-chat
Practice : Identify these disorders
31
OBJ 18 : Explain the difference
between the 2 kinds of Translocation
Abnormalities
• An individual gains an additional
chromosome or has 1 chromosome
abnormally attached to another.
• 2 Types: (1) Balanced translocation
carrier- is an individual who has 46
chromosomes , but 1 chromosomes is
attached at the wrong site. Because the
carrier has the correct number total, there
is no apparent phenotype. But the
offspring are not so lucky.
Translocation Abnormalities
• (2) Unbalanced translocation syndrome is
the result of an offspring receiving a sex
chromosome from a Balanced trans location carrier. The result is an individual
with 47chromosomes.
• Phenotype for these individuals is exactly
the same as Down’s, Trisomy 21 – making
up about 2% of Downs individuals
• Genetic screening can identify Balanced
translocation carriers – preventing this
type of translocation.
Process of Translocation
32
Translocation carrier and possible combinations
of translocated chromosomes: 45XY,1(14:21)
• Balanced Carrier -
Unbalanced Syndromes
Translocation disorders
• Robertsonian Translocation
OBJ 19 : Define Mosaicism and
describe how it can occur
• Mosaicism occurs when Nondisjunction takes
place in mitotic cell division after fertilization.
The result is that body cells vary in the total
number of chromosomes – some 46 or 47. If
there is a large percentage of body cells with the
abnormal number of chromosomes, the
individual is more affected, and has a more
pronounced phenotype.
• Example of a mosaic female with Down’s is
46XX/47XX21+
33
Distribution of Mosaicism
Cutaneous Mosaicism
34
OBJ 20 : Explain the process of
formation of Isochromosomes
• Isochromosomes develop when a cell
divides horizontally instead of vertically
leaving mismatched chromosomes with
long and short arm abnormalities.
• Some isochromosomes have about the
same effect as translocation abnormalities.
Turner’s syndrome may occur this way.
Karyotype of a tumor cell with Isochromosomes
39X with 9 abnormalities
www.medscape .com/viewarticle/405696_3
Monosomy at -3,4,
10,13,18
Trisomy – 7
Subtle Abberations –
1q, 8p, 6&23q
35
Karyotype for Adenocarcinoma of the
lung: 57X0 and 22 abnormalities
• www.path.cam.ac.uk/.../NCI-H1395.html
Testing for Genetic Disorders
OBJ 21 : Maternal Serum AlfaFetoprotein: describe the procedure ,
when it can be done, and what
disorders are recognized with this test
• AFP – Alpha –fetoprotein is a glycoprotein
produced by the fetal liver. Done week 15 of
pregnancy during routine visit .
• Is decreased in chromosomal disorders,
specifically Trisomy 21.
• Is elevated more than twice the value of normal
in spinal cord defects.
• Has a 30% rate of false positives. Therefore,
positives are followed up with amniotic fluid
assessment.
36
OBJ 22: Describe the test, when in
pregnancy it can be done, and
disorders which can be identified
by Chorionic Villi Sampling
• Chorionic villi sampling – involves the
retrieval and analysis of chorionic villi for
DNA analysis. Has no false positives.
• Done commonly at 8-10 weeks of
pregnancy. May be done as early as 5
weeks. Results may be received as soon
as the next day.
Chorionic Villi Sampling (CVS)
• Risks : excessive bleeding resulting in
pregnancy loss (less than 1%). Infections,
uterine contractions or vaginal bleeding.
• If mom is Rh neg, must receive Rhogam
after test.
CVS or Chorionic Villi Sampling
• Not all inherited diseases can be detected
by CVS. It works for abnormal
chromosomes, Non disjunction, and
disorders where the gene location is
known. The test does not reveal the
extent of spinal cord disorders.
• Table 7.2 of your text gives details of
genetic disorders that can be identified by
CVS
37
CVS: A catheter is inserted vaginally
and chorion is aspirated
OBJ 23 : Compare and contrast
Amniocentesis and CVS for when it
can be done in pregnancy, what
disorders can be identified, and the
rate of pregnancy loss with the two
tests
• Amniocentesis is the withdrawal of amnionic
fluid thru the abdominal wall for analysis at 14th
to 16th week of pregnancy. Carries a risk of less
than .5% of pregnancy loss ( which is better than
CVS). Is recommended for the follow up of
positive AFP tests.
Results of Amniocentesis
• Results that can be revealed by Amnio include:
- Karyotyping the skin cells in the fluid.
- AFP and acetylcholinesterace which is
used as a double check for false positives of
AFP.
- Hexosaminidase A will identify TaySachs disease
- Fetal lung maturity determined by L-S
Ratio
38
The Procedure
OBJ 24 : Describe post procedural care
for CVS and Amniocentesis
• Observe for about 30 minutes after
procedure to determine if the procedure
will cause bleeding or uterine contractions.
• Check Fetal heart tones to make sure
there is no fetal distress
• If Mom is Rh negative, give Rhogam after
the procedure to prevent isoimmunization
Genetic Counseling
• A specialty nursing role. The role requires
special knowledge of genetics, and a masters in
nursing. Jobs are found in conjunction with
genetic testing centers.
• Usually couples seek genetic counseling after
they have had an affected child.
39
OBJ 25 : Describe the nursing process
in genetic counseling
• Assessment involves taking a family
history, Physical assessment of parents
and affected children, assistance with lab
tests and interpretations of data. (See
table 7.1 in text for specific characteristics
of newborns with genetic disorders)
• Analysis usually involves decisional
conflict and knowledge deficits. Other
Nursing diagnoses are listed in the text.
• Outcomes involve goals that are realistic
and consistent with the couple’s life style.
Nursing process
• Implementation : Provide information
about testing and genetic disorders.
Results should be related ASAP after
testing.
• Support people affected to make informed
reproductive decisions. May involve grief
counseling, or some parents may
experience loss of self esteem.
• Maintain confidentiality in informing
appropriate people.
• Identify support organization
Nursing Process
• Evaluation – usually successful if the
couple feels they have coped with
disorder, understand the possibility of
future pregnancies resulting in additional
genetic disorders.
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