GENETICS

INTRODUCTION

Inherited or genetic disorders are disorders that can be passed from one generation

to the next. They result from some disorder in gene or chromosome structure and occur in

5% to 6% of newborns. Genetics is the study of the way such disorders occur.

Cytogenetics is the study of chromosomes by light microscopy and the method by which

chromosomal aberrations are identified.

Genetic disorders may occur at the moment an ovum and sperm fuse or even

earlier, in the meiotic division phase of the gametes (ovum and sperm). Some genetic

abnormalities are so severe that normal fetal growth cannot continue past

that point. This early cell division is so precarious a process, in fact, that up to 50% of

first-trimester spontaneous miscarriages may be the result of chromosomal abnormalities

(Schorge et al., 2008). Other genetic disorders do not affect life in utero, so the result of

the disorder becomes apparent only at the time of fetal testing or after birth.

Women having in vitro fertilization (IVF) can have both the egg and sperm

examined for genetic disorders of single gene or chromosome concerns before

implantation . In the near future, it may be possible not only to identify aberrant genes for

disorders this way but also to insert healthy genes in their place using stem cell

implantation. Gene replacement therapy this way is encouraging in the treatment of

blood, spinal cord, and immunodeficiency syndrome (Cardone, 2007). Women can

arrange to have a newborn’s cord blood frozen and banked to be available for bone

marrow or other cell transplantation procedures in the future . As stem cells for

replacement therapy can be obtained from menstrual blood, this also may be a future

contribution source .

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NATURE OF INHERITANCE

Genes are the basic units of heredity that determine both the physical and

cognitive characteristics of people. Composed of segments of DNA (deoxyribonucleic

acid), they are woven into strands in the nucleus of all body cells to form chromosomes.

In humans, each cell, with the exception of the sperm and ovum, contains 46

chromosomes (22 pair of autosomes and 1 pair of sex chromosomes). Spermatozoa and

ova each carry only half of the chromosome number, or 23 chromosomes.

For each chromosome in the sperm cell, there is a like chromosome of similar

size and shape and function (autosome, or homologous chromosome) in the ovum.

Because genes are always located at fixed positions on chromosomes,

two like genes (alleles) for every trait are represented in the ovum and sperm on

autosomes. The one chromosome in which this does not occur is the chromosome

for determining gender. If the sex chromosomes are both type X (large symmetric) in the

zygote formed from the union of a sperm and ovum, the individual is female. If one sex

chromosome is an X and one a Y (a smaller type), the individual is a male .

A person’s phenotype refers to his or her outward appearance or the expression of

genes. A person’s genotype refers to his or her actual gene composition. It is impossible

to predict a person’s genotype from the phenotype, or outward appearance

Photomicrographs Of Human Chromosomes (Karyotypes). (A) Normal Female

Karyotype. (B) Normal Male Karyotype.

MENDELIAN INHERITANCE:

DOMINANT AND RECESSIVE PATTERNS

The principles of genetic inheritance of disease are the same as those that

govern genetic inheritance of other physical characteristics, such as eye or hair color.

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These principles were discovered and described by Gregor Mendel, an Austrian

naturalist, in the 1800s and are known as mendelian laws.

A person who has two like genes for a trait—two healthy genes, for example

(one from the mother and one from the father)—on two like chromosomes is said to be

homozygous for that trait. If the genes differ (a healthy gene from the mother and an

unhealthy gene from the father, or vice versa), the person is said to be heterozygous for

that trait. Many genes are dominant in their action over others. When paired with

nondominant (recessive) genes, dominant genes are always expressed in preference to the

recessive genes. An individual with two homozygous genes for a dominant trait is said to

be homozygous dominant; an individual with two genes for a recessive trait is

homozygous recessive.

INHERITANCE OF DISEASE

Since the entire human genome has been mapped, an increasing number of types of

disease inheritance have been identified.

AUTOSOMAL DOMINANT DISORDERS

Although more than 3000 autosomal dominant disorders are known, only a few

are commonly seen because the majority of these are not compatible with life after birth.

Most of those that do occur cause structural defects. With an autosomal

dominant condition, either a person has two unhealthy genes (is homozygous dominant)

or is heterozygous, with the gene causing the disease stronger than the corresponding

healthy recessive gene for the same trait.

If a person who is heterozygous for an autosomal dominant trait (the usual pattern)

mates with a person who is free of the trait, as shown in Figure 7.2A, the chances are

even (50%) that a child born to the couple would have the disorder or would be disease

and carrier free (i.e., carrying no affected gene forthe disorder).

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Two heterozygous people with a dominantly inherited disorder are unlikely to choose

each other as reproductive partners. If they do, however, their chances of having children

free from the disorder decline. There would be only a 25% chance of a child’s being

disease and carrier free, a 50% chance that the child would have the disorder as both

parents do, and a 25% chance that a child would be homozygous dominant (i.e., have two

dominant disorder genes), a condition that probably would be incompatible with life

Huntington disease is a progressive neurologic disorder, characterized by loss of

motor control and intellectual deterioration, that is a heterozygous inherited autosomal

dominant disorder. The symptoms do not manifest themselves until people reach 35 to 45

years of age. Because some people who might develop this disorder want to know before

that age if they will develop the disease, a test is now available to analyze for the specific

gene on chromosome 4 that causes the disorder . Unfortunately, there is no cure for

Huntington disease, so potentially affected individuals have to make the difficult choice

to decide to have the analysis or not, as there is nothing but palliative care for this

ultimately fatal disorder.

Other examples of autosomal dominantly inherited disorders include

facioscapulohumeral muscular dystrophy (a disorder that results in muscle weakness), a

form of osteogenesis imperfecta (a disorder in which bones are exceedingly brittle),

Marfan syndrome (a disorder of connective tissue that results in an individual being

thinner and taller than usual and perhaps with associated heart disorders (Stuart &

Williams, 2007), and breast and breast/ovarian cancer syndrome that accounts for 5% to

10% of breast cancer in women .

In assessing family genograms (maps of family relationships) for the incidence of

inherited disorders, a number of common findings are usually discovered when a

dominantly inherited pattern is present in a family:

1. One of the parents of a child with the disorder also will have the disorder (a

vertical transmission picture).

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2. The sex of the affected individual is unimportant in terms of inheritance.

3. There is usually a history of the disorder in other family members.

AUTOSOMAL RECESSIVE INHERITANCE

More than 1500 autosomal recessive disorders have been identified. In contrast

to structural disorders, these tend to be biochemical or enzymatic. Such diseases do not

occur unless two genes for the disease are present (i.e., a homozygous recessive pattern).

Examples include cystic fibrosis, adrenogenital

syndrome, albinism, Tay-Sachs disease, galactosemia, phenylketonuria, limb-girdle

muscular dystrophy, and Rhfactor incompatibility.

An example of autosomal recessive inheritance is Both parents are disease free of

cystic fibrosis, but both are heterozygous in genotype, so they carry a recessive gene for

cystic fibrosis. When this genetic pattern occurs, there is a 25% chance that a child born

to a couple will be disease and carrier free (homozygous dominant for the healthy gene);

a 50% chance that the child will be, like the parents, free of disease but carrying the

unexpressed disease gene (heterozygous); and a 25% chance that the child will have the

disease (homozygous recessive).

Suppose a woman with the heterozygous genotype .A mates with a man who has

no trait for cystic fibrosis. There is a 50% chance that a child born to them will be

completely disorder and carrier free, like the father. Likewise, there is a 50% chance that

their child will be heterozygous (i.e., a carrier), like the mother . There is no chance in

this instance that any of their children will have the disorder. However, they should be

counseled that if a child of theirs who carries the trait has children with a sexual partner

who also has a recessive gene for the trait, grandchildren could manifest the disease.

Cystic fibrosis is caused by an errant gene on the seventh chromosome. As many as 1 in

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every 29 Caucasian people carries the trait. People who are concerned as to whether they

have a recessive gene for the disorder can have a DNA analysis to reveal their status .

Twenty years ago, most children with cystic fibrosis died in early childhood and

therefore never reached childbearing age. Today, with good management, such children

can live to adulthood and have children of their own. If a person with cystic fibrosis

(homozygous recessive) should choose a sexual partner without the trait, none of their

children would have the disorder, but all would be carriers of a recessive gene for the

disorder .

If a person with cystic fibrosis mated with a person with an unexpressed gene for

the disease, there would be a 50% chance that a child would have the disorder

(homozygous) and a 50% chance that he or she would be heterozygous for the disorder .

If a person with the disorder mated with a person who also had the disorder, as shown

there is a 100% chance that their child would have the disorder. when family genograms

are assessed for the incidence of inherited disease, situations commonly discovered when

a recessively inherited disease is present in the family include:

1. Both parents of a child with the disorder are clinically free of the disorder.

2. The sex of the affected individual is unimportant in

terms of inheritance.

3. The family history for the disorder is negative—that is, no one can identify

anyone else who had it.

4. A known common ancestor between the parents sometimes

exists. this explains how both male and female came to possess a like gene for the

disorder a typical genogram of a family with an autosomal recessive inherited disorder.

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X-LINKED DOMINANT INHERITANCE

Some genes for disorders are located on, and therefore transmitted only by, the

female sex chromosome (the x chromosome). there are about 300 known disorders

associated this way and their transmission is termed x-linked inheritance. If the affected

gene is dominant, only one x chromosome with the trait need be present for symptoms of

the disorder to be manifested . Family characteristics seen with this type of inheritance

usually include:

1. All individuals with the gene are affected (the gene is dominant).

2. All female children of affected men are affected; all male children of affected

men are unaffected.

3. It appears in every generation.

4. All children of homozygous affected women are affected. fifty percent of the

children of heterozygous affected women are affected an example of a disease in this

group is alport’s syndrome, a progressive kidney failure disorder.

X-LINKED RECESSIVE INHERITANCE

The majority of x-linked inherited disorders are not dominant, but recessive. when

the inheritance of a recessive gene comes from both parents (homozygous recessive) it

appears to be incompatible with life. Therefore, females who inherit the affected gene

will be heterozygous, and, because a normal gene is also present, the expression of the

disease will be blocked. On the other hand, because males have only one X chromosome,

the disease will be manifested in any male children who receive the affected gene from

their mother.

Hemophilia A and Christmas disease (blood-factor deficiencies),

color blindness, Duchenne (pseudohypertrophic) muscular dystrophy, and fragile X

syndrome (a cognitive challenge syndrome) are examples of this type of inheritance.

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Such a pattern is in which the mother has the affected gene on one of her X

chromosomes and the father is disease-free. When this occurs, the chances are 50% that a

male child will manifest the disease and 50% that a female child will carry the disease

gene. If the father has the disease and chooses a sexual partner who is free of the disease

gene, the chances are 100% that a daughter will have the sexlinked recessive gene, but

there is no chance that a son will have the disease .

When X-linked recessive inheritance is present in a family,a family genogram will

reveal:

1. Only males in the family will have the disorder.

2. A history of girls dying at birth for unknown reasons often exists (females who

had the affected gene on both X chromosomes).

3. Sons of an affected man are unaffected.

4. The parents of affected children do not have the disorder.

Y-LINKED INHERITANCE.

Although genes responsible for feature such as height and tooth size are found on

the Y chromosome, tall stature and perhaps aggressive personality are the only consistent

phenotypic features associated with having an extra Y chromosome (karyotype 47XYY) .

MULTIFACTORIAL (POLYGENIC) INHERITANCE

Many childhood disorders such as heart disease, diabetes, pyloric stenosis, cleft

lip and palate, neural tube disorders, hypertension, and mental illness tend to have a

higher-than usual incidence in some families. They appear to occur from multiple gene

combinations possibly combined with environmental factors. Diabetes has been

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extensively studied in this regard. Certain human lymphocyte antigens (HLAs) inherited

from both parents appear to play a role in genetic susceptibility to diabetes mellitus.

Children who will develop diabetes mellitus can be shown to have an increased

frequency of HLA B8, B15, DR3, and DR4 on chromosome 6.

They lack DR2, an HLA that appears to be protective against

diabetes mellitus. Diseases caused by multiple factors this way do not follow

Mendelian laws because more than a single gene or HLA is involved. It may be more

difficult for parents to understand why these disorders occur because their incidence is so

unpredictable. A family history, for instance, may reveal no set pattern.

Some of these conditions have a predisposition to occur more frequently in one

sex (cleft palate occurs more often in girls than boys), but they can occur in either sex.

MITOCHONDRIAL INHERITANCE.

Mitochondria are cell organelles that are found outside the cell nucleus. They are

inherited solely from the cytoplasm of the ovum. Male carriers cannot

pass a disorder carried in the mitochondria to any of their children. Females, on the other

hand, will pass mitochondrial disorders to 100% of their children. A number of rare

myopathies (muscle diseases) are inherited in this way.

CHROMOSOMAL ABNORMALITIES

(Cytogenic Disorders)

In some instances of genetic disease, the abnormality occurs not because of

dominant or recessive gene patterns but through a fault in the number or structure of

chromosomes which results in missing or distorted genes. When chromosomes

are photographed and displayed, the resulting arrangement is termed a karyotype. The

number of chromosomes and specific parts of chromosomes can be identified by

Karyotyping or by a process termed fluorescent in situ hybridization (FISH).

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NONDISJUNCTION ABNORMALITIES

Meiosis is the type of cell division in which the number of chromosomes in the

cell is reduced to the haploid (half) number for reproduction (i.e., 23 rather than 46

chromosomes). All sperm and ova undergo a meiosis cell division early in formation.

During this division, half of the chromosomes are attracted to one pole of the cell and

half to the other pole. The cell then divides cleanly, with 23 chromosomes in the first new

cell and 23 chromosomes in the second new cell.

Chromosomal abnormalities occur if the division is uneven (nondisjunction). The

result may be that one new sperm cell or ovum has 24 chromosomes and the other has

only 22 (Fig. 7.9). If a spermatozoon or ovum with 24 or 22 chromosomes fuses with a

normal spermatozoon or ovum, the zygote (sperm and ovum combined) will have either

47 or 45 chromosomes, not the normal 46. The presence of 45 chromosomes does not

appear to be compatible with life, and the embryo or fetus probably will be aborted.

Down syndrome (trisomy 21) (47XX21_ or 47XY21_) is an example of a disease in

which the individual has 47 chromosomes. There are three rather than two copies of

chromosome 21 .

The incidence of Down syndrome increases with advanced maternal age and is

highest if the mother is older than 35 years and the father is older than 55. Thus, aging

seems to present an obstacle to clean cell division. The incidence is 1:100 in women older

than 40 years, compared with 1:1500 in women younger than 20 years . Other examples

of cell nondisjunction include trisomy 13 and trisomy 18 . If nondisjunction occurs in the

sex chromosomes, other types of abnormalities occur. Turner and Klinefelter syndromes

are the most common types.

In Turner syndrome (45XO), marked by webbed neck, short stature, sterility, and

possibly cognitive challenge, the individual, although female, has only one X

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chromosome (or has two X chromosomes but one is defective). Her appearance

(phenotype) is female because of the one X chromosome.

In Klinefelter’s syndrome (marked by sterility and possibly cognitive challenge),

the individual has male genitals but the sex chromosomal pattern is 47XXY or an extra X

chromosome is present.

DELETION ABNORMALITIES

Deletion abnormalities are a form of chromosome disorder in which part of a

chromosome breaks during cell division, causing the affected person to have the normal

number of chromosomes plus or minus an extra portion of a chromosome,

such as 45.75 chromosomes or 47.5. For example, in cri-du-chat syndrome (46XY5q_),

one portion of chromosome 5 is missing.

TRANSLOCATION ABNORMALITIES

Translocation abnormalities are perplexing situations in which a child gains an

additional chromosome through another route. A form of Down syndrome occurs as an

example of this. In this instance, one parent of the child has the correct number of

chromosomes (46), but chromosome 21 is misplaced; it is abnormally attached to another

chromosome, such as chromosome 14 or 15. The parent’s appearance and functioning are

normal because the total chromosome count is a normal 46. He or she is termed a

balanced translocation carrier.

If, during meiosis, this abnormal chromosome 14 (carrying the extra 21

chromosome) and a normal chromosome 21 from the other parent are both included in

one sperm or ovum, the resulting child will have a total of 47 chromosomes because of

the extra number 21. Such a child is said to have an unbalanced translocation syndrome.

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The phenotype (appearance) of the child will be indistinguishable from that of a child

with the form of Down syndrome that occurs from simple non disjunction.

About 2% to 5% of children with Down syndrome have this type of chromosome

pattern. It is important that parents who are translocation carriers are identified because

their chance of having a child born with Down syndrome is

higher than normal and not associated with aging. If the father is the carrier, this risk is

about 5%; if the mother is the carrier, the risk is about 15%. As many as 15% of couples

who have frequent early spontaneous miscarriages may have this type of chromosomal

aberration.

MOSAICISM

Usually, a nondisjunction abnormality occurs during the meiosis stage of cell

division, when sperm and ova halve their number of chromosomes. Mosaicism is an

abnormal condition that is present when the nondisjunction disorder occurs

after fertilization of the ovum, as the structure begins mitotic (daughter-cell) division. If

this occurs, different cells in the body will have different chromosome counts. The extent

of the disorder depends on the proportion of tissue with normal

chromosome structure to tissue with abnormal chromosome constitution. Children with

Down syndrome who have near normal intelligence may have this type of pattern. The

occurrence of such a phenomenon at this stage of development

suggests that a teratogenic (harmful to the fetus) condition, such as x-ray or drug

exposure, existed at that point to disturb normal cell division. This genetic pattern in a

female with Down syndrome caused by mosaicism would be abbreviated

as 46XX/47XX21_ to show that some cells contain46 and some 47 chromosomes.

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ISOCHROMOSOMES

If a chromosome accidentally divides not. Any individual concerned about the

possibility of transmitting a disease to his or her children should have access to genetic

counseling for advice on the inheritance of disease.

Such counseling can serve to:

• Provide concrete, accurate information about the process of inheritance and inherited

disorders

• Reassure people who are concerned that their child may inherit a particular disorder that

the disorder will not occur

• Allow people who are affected by inherited disorders to make informed choices about

future reproduction

• Offer support to people who are affected by genetic disorders

GENETIC COUNSELING

Genetic counseling is the process, by which patients or relatives, at risk of an

inherited disorder, are advised of the consequences and nature of the disorder, the

probability of developing or transmitting it, and the options open to them in management

and family planning. This complex process can be separated into diagnostic (the actual

estimation of risk) and supportive aspects.

COUNSELING SESSION STRUCTURE

The goals of genetic counseling are to increase understanding of genetic diseases,

discuss disease management options, and explain the risks and benefits of testing.

Counseling sessions focus on giving vital, unbiased information and non-directive

assistance in the patient's decision making process.

Seymour Kessler, in 1979, first categorized sessions in five phases: an intake

phase, an initial contact phase, the encounter phase, the summary phase, and a

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follow-up phase. The intake and follow-up phases occur outside of the actual counseling

session. The initial contact phase is when the counselor and families meet and build

rapport. The encounter phase includes dialogue between the counselor and the client

about the nature of screening and diagnostic tests. The summary phase provides all the

options and decisions available for the next step. If counselees wish to go ahead with

testing, an appointment is organized and the genetic counselor acts as the person to

communicate the results.

Can result in making individuals feel “well” or free of guilt for the first time in

their lives if they discover that the disorder they were worried about was not an inherited

one but was rather a chance occurrence. In other instances, counseling results in

informing individuals that they are carriers of a trait that is responsible for a child’s

condition. Even when people understand that they have no control over this, knowledge

about passing a genetic disorder to a child can cause guilt and self-blame. Marriages and

relationships can end unless both partners receive adequate support.

It is essential that information revealed in genetic screening be kept confidential,

because such information could be used to damage a person’s reputation or harm a future

career or relationship. This necessity to maintain confidentiality prevents health care

providers from alerting other family members

about the inherited characteristic unless the member requesting genetic assessment has

given consent for the information to be revealed. In some instances, a genetic history

reveals information, such as that a child has been adopted or is the result of artificial

insemination, or that a current husband is not the child’s father information that a family

doesn’t want revealed.

-- The member of the family seeking counseling has the right to decide

whether this information may be shared with other family members.

-- The ideal time for counseling is before a first pregnancy. Some couples take

this step even before committing themselves to marriage so they can offer not to involve

their partner in a marriage if children of the marriage would be subject to a serious

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inherited disorder. Other couples first become aware of the need for genetic counseling

after the birth of a first child with a disorder. It is best if they receive counseling before a

second pregnancy. A couple may not be ready for this, however, until the initial shock of

their first child’s condition and the grief reaction that may accompany it have run their

course.

Only then are they ready for information and decision making Even if a couple

decides not to have any more children, it is important that they know that genetic

counseling is available should their decision change. Also be certain that they are aware

that as their children reach reproductive age, they, too, may benefit from genetic

counseling. Couples who are most apt to benefit from a referral for genetic testing or

counseling include:

• A couple who has a child with a congenital disorder or an inborn error of

metabolism. Many congenital disorders occur because of teratogenic invasion during

pregnancy that has gone unrecognized. Learning that the abnormality occurred by chance

rather than inheritance is important, because the couple will not have to spend the

remainder of their childbearing years in fear that another child may be born with the

disorder . If a definite teratogenic agent, such as a drug a woman took during pregnancy,

can be identified, the couple can be advised about preventing this occurrence in a future

pregnancy.

• A couple whose close relatives have a child with a genetic disorder such as a

translocation disorder or an inborn error of metabolism. It is difficult to predict the

expected occurrence of many “familial” or multifactorial disorders. In these instances,

counseling should be aimed at educating the couple about the disorder, treatment

available, and the prognosis or outcome of the disorder. Based on this information, the

couple can make an informed reproductive choice about children.

• Any individual who is a known balanced translocation carrier. Understanding

of his or her own chromosome structure and the process by which future children could

be affected can help such an individual make an informed choice about reproduction or

can alert him or her to the importance of fetal karyotyping during any future pregnancy

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• Any individual who has an inborn error of metabolism or chromosomal

disorder. Any person with a disease should know the inheritance pattern of the disease

and, like those who are balanced translocation carriers, should be aware if prenatal

diagnosis is possible for his or her particular disorder.

• A consanguineous (closely related) couple. The more closely related are two

people, the more genes they have in common, so the more likely it is that a recessively

inherited disease will be expressed. A brother and sister, for example,

have about 50% of their genes in common; first cousins have about 12% of their genes in

common.

• Any woman older than 35 years and any man older than 55 years. This is

directly related to the association between advanced parental age and the occurrence of

Down syndrome.

• Couples of ethnic backgrounds in which specific illnesses are known to occur.

Mediterranean people, for example, have a high incidence of thalassemia, a blood

disorder; those with a Chinese ancestry have a high incidence of glucose-6-

phosphate dehydrogenase (G6PD) deficiency, a blood disorder where destruction of red

cells can occur .

NURSING RESPONSIBILITIES

Nurses play important roles in assessing for signs and symptoms of genetic

disorders, in offering support to individuals who seek genetic counseling, and in helping

with reproductive genetic testing procedures by such actions as:

• Explaining to a couple what procedures they can expect to

undergo

• Explaining how different genetic screening tests are done and when they are usually

offered

• Supporting a couple during the wait for test results

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• Assisting couples in values clarification, planning, and decision making based on test

results

A great deal of time may need to be spent offering support for a grieving couple

confronted with the reality of how tragically the laws of inheritance have affected their

lives. Genetic counseling is a role for nurses, however, only if they

are adequately prepared in the study of genetics because without this background, genetic

counseling can be dangerous and destructive .

Whether one is acting as a nursing member of a genetic counseling team or as a

genetic counselor, some common principles apply. First, the individual or couple being

counseled needs a clear understanding of the information provided.

People may listen to the statistics of their situation (“Your child has a 25% chance of

having this disease”) and construe a “25% chance” to mean that if they have one

child with the disease, they can then have three other children without any worry. A

25% chance, however, means that with each pregnancy there is a 25% chance that the

child will have the disease (chance has no “memory” of what has already happened). It is

as if the couple had four cards, all aces, with the ace of spades representing the disease.

When a card is drawn from the set of four, the chance of it being the ace of spades

is 1 in 4 (25%). When the couple is ready to have a second child, it is as if the card drawn

during the first round is returned to the set, so the chance of drawing the ace of spades in

the second draw is exactly the same as in the first draw. Similarly, the couple’s chances

of having a child with the disease remain 1 in 4 in each successive pregnancy.

Second, it is never appropriate for any health care provider to impose his or her

own values or opinions on others. Individuals with known inherited diseases in their

family must face difficult decisions, such as how much genetic testing

to undergo or whether to terminate a pregnancy that will result in a child with a specific

genetic disease. Be certain that couples have been made aware of all the options available

to them; then leave them to think about the options and make

their own decisions by themselves. Help them to understand that nobody is judging their

decision because they are the ones who must live with the decision

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ASSESSMENT FOR GENETIC DISORDERS

Genetic assessment begins with careful study of the pattern of inheritance in a

family. A history, physical examination of family members, and laboratory analysis, such

as Karyotyping or DNA analysis, are performed to define the extent of the problem and

the chance of inheritance.

History

Taking a health history for a genetic diagnosis is often difficult because the facts

detailed may evoke uncomfortable emotions such as sorrow, guilt, or inadequacy in

parents. Try, however, to obtain information and document diseases in family members

for a minimum of three generations. Remember to include half brothers and sisters or

anyone related in any way as family. Document the mother’s age because some disorders

increase in incidence with age. Document also whether the parents are consanguineous or

related to each other.

Documenting the family’s ethnic background can reveal risks for certain disorders

that occur more commonly in some ethnic groups than others. If the couple seeking

counseling is unfamiliar with their family history, ask them to talk to senior family

members about other relatives (grandparents, aunts, uncles) before they come for an

interview. Have them ask specifically for instances of spontaneous miscarriage or

children in the family who died at birth. In many instances, these children died of

unknown chromosomal disorders or were miscarried because of one of the 70 or more

known chromosomal disorders that are inconsistent with life. Many people have only

sketchy information about their families, such as, “The baby had some kind of nervous

disease” or “Her heart didn’t work right.” Attempt to obtain more information by asking

the couple to describe the appearance or activities of the affected individual or asking for

permission to obtain health records. An extensive prenatal history of any affected person

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should be obtained to determine whether environmental conditions could account for the

condition. When a child is born dead, parents are advised to have a chromosomal analysis

and autopsy performed on the infant.

If at some future date they wish genetic counseling, this would allow their

genetic counselor to have additional medical information.

PHYSICAL ASSESSMENT

Because genetic disorders often occur in varying degrees of expression, a

careful physical assessment of any family member with a disorder, that child’s siblings,

and the couple seeking counseling is needed. It is possible for an individual to have a

minimal expression of a disorder that has gone previously undiagnosed. During

inspection, pay particular attention to certain body areas, such as the space between the

eyes; the height, contour, and shape of ears; the number of fingers and toes, and the

presence of webbing.

Dermatoglyphics (the study of surface markings of the skin) can also be

helpful. Note any abnormal fingerprints or palmar creases as these are present with some

disorders. Abnormal hair whorls or coloring of hair can also be present. Careful

inspection of newborns is often sufficient to identify a child with a potential

chromosomal disorder. Infants with multiple congenital anomalies, those born at less than

35 weeks’ gestation, and those whose parents have had other children with chromosomal

disorders need extremely close assessment.

DIAGNOSTIC TESTING

Many diagnostic tests are available to provide important clues about possible

disorders . Before pregnancy, karyotyping of both parents and an already affected child

provides a picture of the chromosome pattern that can be used to predict occurences in

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future children. Once a woman is pregnant, several other tests may be performed to help

in the prenatal diagnosis of a genetic disorder. These include maternal serum alpha-

fetoprotein (MSAFP), chronic villi sampling (CVS), amniocentesis, percutaneous

umbilical blood sampling (PUBS), ultrasound, and fetoscopy.

KARYOTYPING

For karyotyping, a sample of peripheral venous blood or a scraping of cells from the

buccal membrane is taken. Cells are allowed to grow until they reach metaphase, the

most easily observed phase. Cells are then stained, placed under a microscope, and

photographed. Chromosomes are identified according to size, shape, and stain; cut from

the photograph, and arranged as in Figure 7.1. Any additional, lacking, or abnormal

chromosomes can be visualized by this method. A newer method of staining, FISH,

allows karyotyping to be done immediately, rather than waiting for the cells to reach

metaphase. This makes it possible for a report to be obtained in only 1 day. Fetal skin

cells can be obtained by amniocentesis or CVS. A few fetal cells circulate in the maternal

bloodstream,

most noticeably trophoblasts, lymphocytes, and granulocytes.

They are present but few in number during the first and second trimesters but

plentiful during the third trimester. Such cells can be cultured and used for genetic testing

for such disorders as the trisomies.

MATERNAL SERUM SCREENING

Alpha-fetoprotein (AFP) is a glycoprotein produced by the fetal liver that reaches

a peak in maternal serum between the 13th and 32nd week of pregnancy. The level is

elevated with fetal spinal cord disease (more than twice the value of the mean for that

gestational age) and is decreased in a fetal chromosomal disorder such as trisomy 21.

Most pregnant women have an MSAFP test done routinely at the 15th week of

pregnancy. If the result is abnormal, amniotic fluid is then assessed. Unfortunately, the

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MSAFP test has a false-positive rate of about 30% if the date of conception is not well

documented. Use of a “triple study” (AFP, estriol, and hCG) reduces this false-positive

rate, although false-positive reports still occur.

Analysis of a pregnancy-associated plasma protein A, which is also increased with

a Down syndrome pregnancy, and measurement of the fetal neck thickness by ultrasound

are still other measures used for analysis if an MSAFP test is positive. Women with an

elevated serum result need support while they wait for ultrasound or amniocentesis

confirmation as they are facing what may be a very grave finding in their infant.

Receiving a false-positive report is unfortunate as it can potentially interfere with the

mother’s bonding with her infant.

CHORIONIC VILLI SAMPLING.

CVS is a diagnostic technique that involves the retrieval and analysis of chorionic

villi from the growing placenta for chromosome or DNA analysis. The test is highly

accurate and yields no more false-positive results than does amniocentesis. Although this

procedure may be done as early as week 5 of pregnancy, it is more commonly done at 8

to 10 weeks. With this technique, the chorion cells are located by ultrasound. A thin

catheter is then inserted vaginally, or a biopsy needle is inserted abdominally or

intravaginally, and a number of chorionic cells are removed for analysis . CVS carries a

small risk (less than 1%) of causing excessive bleeding, leading to pregnancy loss. There

have been some instances of children being born with missing limbs after the procedure

(limb reduction syndrome). This has occurred with a high enough frequency that women

need to be well informed of these risks beforehand.

After CVS, instruct a woman to report chills or fever suggestive of infection or

symptoms of threatened miscarriage (uterine contractions or vaginal bleeding). Women

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with an Rh-negative blood type need Rh immune globulin administration after the

procedure to guard against isoimmunization in the fetus.

The cells removed in CVS are karyotyped or submitted for DNA analysis to reveal

whether the fetus has a genetic disorder. Because chorionic villi cells are rapidly

dividing, results are available quickly, perhaps as soon as the next day.

If a twin or multiple pregnancy is present, with two or more separate placentas,

cells should be removed separately from each placenta. Because fraternal twins are

derived from separate ova, one twin could have a chromosomal abnormality while the

other does not. Not all inherited diseases can be detected by CVS. Be certain that parents

understand that only those disorders involving

abnormal chromosomes or non disjunction, and those whose specific gene location is

known, can be identified by CVS. The test is not apt to reveal the extent of spinal cord

abnormalities, for example.

Chromosomal disorders that can be diagnosed prenatally through karyotyping.

Additional disorders that can be identified by DNA analysis are retinoblastoma,

myotonic dystrophy, Huntington disease, sickle cell anemia, thalassemia, and Duchenne

muscular dystrophy.

The decision to undergo CVS is a major one for a couple. As a rule, they are not

making a decision simply for CVS. If the CVS reveals that their child is abnormal, they

then have to make a second decision about the future of the pregnancy.

Deciding to terminate a pregnancy based on a laboratory finding is rarely easy. The

couple may need a great deal of support with their decision, both to carry it through and

to live with the decision afterward. If they decide not to terminate the pregnancy, they

will need support during the remainder of the pregnancy and in the days following birth.

It may be difficult for a couple to believe that what the test showed is true. Only when

they inspect the baby and see that the test was accurate— the child does have a genetic

disorder—do they see the reality. This can result in long-lasting depression.

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AMNIOCENTESIS

Amniocentesis is the withdrawal of amniotic fluid through the abdominal wall for

analysis at the 14th to 16th week of pregnancy . Because amniotic fluid has reached about

200 mL at this point, enough fluid can be withdrawn for karyotyping of skin cells found

in the fluid as well as an analysis of AFP or acetylcholinesterase. If no

acetylcholinesterase, a breakdown product of blood, is found in the specimen, it confirms

that an elevated AFP level is not a false-positive reading caused by blood in the fluid. For

the procedure, a pocket of amniotic fluid is located by ultrasound. Then a needle is

inserted transabdominally, and about 20 mL of fluid is aspirated. Skin cells in the fluid

are karyotyped for chromosomal number and structure. The level of AFP is analyzed.

Some disorders, such as Tay-Sachs disease, can be identified by the lack of a specific

enzyme, such as hexosaminidase A, in amniotic fluid. Amniocentesis has the advantage

over CVS of carrying only a 0.5% risk of spontaneous miscarriage. Unfortunately, it

usually is not done until the 14th to 16th week of pregnancy.

This may prove to be a difficult time because, by this date, a woman is beginning to

accept her pregnancy and bond with the fetus. In addition, termination of pregnancy

during the second trimester is more difficult than during a first trimester. Support women

while they wait for test results and to make a decision about the pregnancy. Women with

an Rh-negative blood type need Rh immune globulin administration after the procedure

to protect against isoimmunization

in the fetus. All women need to be observed for about 30 minutes after the procedure to

be certain that labor contractions are not beginning and that the fetal heart rate remains

within normal limits. Because amniocentesis is also a common assessment for fetal

maturity.

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PERCUTANEOUS UMBILICAL BLOOD SAMPLING

PUBS, or cordocentesis, is the removal of blood from the fetal umbilical cord at about 17

weeks using an amniocentesis technique. This allows analysis of blood components as

well as more rapid karyotyping than is possible when only skin cells are remove.

FETAL IMAGING

Magnetic resonance imaging (MRI) and ultrasound are diagnostic tools used to

assess a fetus for general size and structural disorders of the internal organs, spine, and

limbs. Because some genetic disorders are associated with physical appearance, both of

these methods may be helpful. Ultrasound is used concurrently with amniocentesis.

FETOSCOPY

Fetoscopy is the insertion of a fiberoptic fetoscope through a small incision in the

mother’s abdomen into the uterus and membranes to visually inspect the fetus for gross

abnormalities. It can be used to confirm an ultrasound finding, to remove skin cells for

DNA analysis, or to perform surgery for a congenital disorder such as a stenosed urethra.

PREIMPLANTATION DIAGNOSIS

Preimplantation diagnosis is possible for in vitro fertilization procedures. It may be

possible in the future for a naturally fertilized ovum to be removed from the uterus by

lavage before implantation and studied for DNA analysis this same way. The ovum

would then be reinserted or not, depending on the findings and the parents’ wishes. This

would provide genetic information extremely early in a pregnancy.

REPRODUCTIVE ALTERNATIVES

Some couples are reluctant to seek genetic counseling because they are afraid they

will be told it would be unwise to have children. Helping them to realize that viable

alternatives for having a family exist allows them to seek the help

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they need. Artificial insemination by donor (AID) is an option for couples if the genetic

disorder is one inherited by the male partner or is a recessively inherited disorder carried

by both partners. AID is available in all major communities and

can permit the couple to experience the satisfaction and enjoyment of a usual pregnancy .

If the inherited problem is one arising from the female partner, surrogate embryo

transfer is an assisted reproductive technique that is a possibility . An oocyte donated by a

friend or relative or provided by an anonymous donor is fertilized by the husband’s sperm

in the laboratory and then implanted into a woman’s uterus. Like AID, donor embryo

transfer offers the couple a chance to experience a normal pregnancy. Use of a surrogate

mother (a woman who agrees to be artificially inseminated, typically by the male

partner’s sperm, and bear a child for the couple) is still another possibility . All of these

procedures are expensive and, depending on individual circumstances, may have

disappointing success rates. Assisted reproductive techniques are

Adoption is an alternative many couples can also find rewarding Choosing to

remain child-free should not be discounted as a viable option. Many couples

who have every reason to think they would have children without a genetic disorder

choose this alternative because they believe their existence is full and rewarding without

the presence of children.

Diagnosis of a disorder during pregnancy with prompt treatment at birth to

minimize the prognosis and outcome of the disorder is another route to explore.

Termination of a pregnancy that reveals a chromosomal or metabolic abnormality

is a final option. Help couples decide on an alternative that is correct for them, not one

that they sense a counselor feels would be best. They need to consider the ethical

philosophy or beliefs of other family members when making their decision, although

ultimately they must do what they believe is best for them as a couple. A useful place to

start counseling is with values clarification, to be certain a couple understands what is

most important to them.

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FUTURE POSSIBILITIES

Stem cell research is looking at the possibility that immature cells (stem cells)

could be implanted into an embryo with a known abnormal genetic makeup, replacing the

abnormal cells or righting the affected child’s genetic composition. Although presently

possible, stem cell research is costly and produces some ethical questions (e.g., although

stem cells can be harvested from cord blood, adult skin cells or menstrual blood, will

these be able to serve as main sources of donor DNA for the new technology?).

LEGAL AND ETHICAL ASPECTS OF GENETIC SCREENING

AND COUNSELING

Nurses can be instrumental in seeing that couples who seek genetic counseling

receive results in a timely manner and with compassion about what their results may

mean to future childbearing. Always keep in mind several legal responsibilities of genetic

testing, counseling, and therapy, including:

• Participation by couples or individuals in genetic screening must be elective.

• People desiring genetic screening must sign an informed consent for the

procedure.

• Results must be interpreted correctly yet provided to the individuals as quickly

as possible.

• The results must not be withheld from the individuals and must be given only to

those persons directly involved.

• After genetic counseling, persons must not be coerced to undergo procedures

such as abortion or sterilization. Any procedure must be a free and individual decision.

Failure to heed these guidelines could result in charges of invasion of privacy, breach of

confidentiality, or psychological injury caused by “labeling” someone or imparting

unwarranted fear and worry about the significance of a disease or carrier state.

If couples are identified as being at risk for having a child with a genetic disorder

and are not informed of the risk and offered appropriate diagnostic procedures (e.g.,

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amniocentesis)they can bring a “wrongful birth” lawsuit if their child is born with the

detected genetic disorder .

COMMON CHROMOSOMAL DISORDERS RESULTING IN PHYSICAL OR

COGNITIVE DEVELOPMENTAL DISORDERS

Several chromosomal disorders, particularly non disjunction disorders, are easily detected

at birth on physical examination. Many of these disorders leave children cognitively

challenged.

TRISOMY 13 SYNDROME (47XY13_ OR 47XX13_)

In trisomy 13 syndrome (Patau syndrome), the child has an extra chromosome 13

and is severely cognitively challenged. The incidence of the syndrome is low,

approximately 0.45 per 1000 live births. Midline body disorders such as cleft lip and

palate, heart defects, particularly ventricular septal defects, and abnormal genitalia are

present . Other common findings include microcephaly with abnormalities of the

forebrain and forehead; eyes that are smaller than normal

(microphthalmos) or absent; and low-set ears. Most of these children do not survive

beyond early childhood.

TRISOMY 18 SYNDROME (47XY18_ OR 47XX18_)

Children with trisomy 18 syndrome have three copies of chromosome 18. The

incidence is approximately 0.23 per 1000 live births. These children are severely

cognitively challenged and tend to be small for gestational age at birth, have markedly

low-set ears, a small jaw, congenital heart defects, and usually misshapen fingers and toes

(the index finger deviates or crosses over other fingers). Also, the soles of their feet are

often rounded instead of flat (rocker-bottom feet). As in trisomy 13 syndrome, most of

these children do not survive beyond early infancy.

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CRI-DU-CHAT SYNDROME (46XX5P_ OR 46XY5P_)

Cri-du-chat syndrome is the result of a missing portion of chromosome 5. In

addition to an abnormal cry, which sounds much more like the sound of a cat than a

human infant’s cry, children with cri-du-chat syndrome tend to have a small head, wide-

set eyes, and a downward slant to the palpebral fissure of the eye. They are severely

cognitively challenged.

TURNER SYNDROME (45X0)

The child with Turner syndrome (gonadal dysgenesis) has only one functional X

chromosome. The child is short in stature and has only streak (small and nonfunctional)

ovaries. She is sterile and with the exception of pubic hair, secondary sex characteristics

do not develop at puberty. The hairline at the nape of the neck is low set, and the neck

may appear to be webbed and short. A newborn may have appreciable edema of the

hands and feet and a number of congenital

anomalies, most frequently coarctation (stricture) of the aorta and kidney disorders.

The incidence of the syndrome is approximately 1 per 10,000 live births. The

disorder can be identified with an ultrasound during pregnancy because of the increased

neck folds. Although children with Turner syndrome may be severely cognitively

challenged, difficulty in this area is more commonly limited to learning disabilities. Socio

emotional adjustment problems may accompany the syndrome because of the lack of

fertility and if the nuchal folds are prominent.

Human growth hormone administration may help children with Turner syndrome

achieve additional height (Baxter et al., 2009). If treatment with estrogen is begun at

approximately 13 years of age, secondary sex characteristics will appear, and

osteoporosis from lack of estrogen during growing years may be prevented. If females

continue taking estrogen for three out of every four weeks, this produces withdrawal

bleeding that results in a menstrual flow. This flow, however, does not correct the

problem of sterility. Gonadal tissue is scant and inadequate for ovulation because of the

basic chromosomal aberration.

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KLINEFELTER SYNDROME (47XXY)

Infants with Klinefelter syndrome are males with an extra X chromosome.

Characteristics of the syndrome may not be noticeable at birth. At puberty, secondary sex

characteristics do not develop; the child has small testes that produce ineffective sperm .

Affected individuals tend to develop gynecomastia (increased breast size) and have an

increased risk of male breast cancer . The incidence is about 1 per 1000 live births.

Karyotyping can be used to reveal the additional X chromosome.

FRAGILE X SYNDROME (46XY23Q_)

Fragile X syndrome is the most common cause of cognitive challenge in males. It

is an X-linked disorder in which one long arm of an X chromosome is defective which

results in inadequate protein synaptic responses (Bear et al., 2008).

The incidence is about 1 in 1000 live births. Before puberty, boys with fragile X

syndrome typically may demonstrate maladaptive behaviors such as hyperactivity and

autism. They may have reduced intellectual functioning,

with marked deficits in speech and arithmetic (Kornman et al., 2007). They may be

identified by the presence of a large head, a long face with a high forehead, a prominent

lower jaw, and large protruding ears. Hyperextensive joints and cardiac

disorders may also be present. After puberty, enlarged testicles may become evident.

Affected individuals are fertile and can reproduce.

Carrier females may show some evidence of the physical and cognitive

characteristics. Although intellectual function from the syndrome cannot be improved,

both folic acid and an antipsychotic drug such as phenothiazines may improve symptoms

of poor concentration and impulsivity.

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DOWN SYNDROME (TRISOMY 21) (47XY21_ OR 47XX21_)

Trisomy 21, the most frequently occurring chromosomal abnormality, occurs in

about 1 in 800 pregnancies. The number of children born with the disorder is

considerably less as many women choose to end pregnancies when the diagnosis

is made . The physical features of children with Down syndrome are so marked that fetal

diagnosis is possible by ultrasound in utero. The nose is broad and flat. The eyelids have

an extra fold of tissue at the inner canthus (an epicanthal fold), and the palpebral fissure

(opening between the eyelids) tends to slant laterally upward. The iris of the eye may

have white specks, called Brushfield spots.

The tongue may protrude from the mouth because the oral cavity is smaller than

usual. The back of the head is flat, the neck is short, and an extra pad of fat at the base of

the head causes the skin to be so loose it can be lifted easily. The ears may be low-set.

Muscle tone is poor, giving the baby a rag-doll appearance. This can be so lax that the

child’s toe can be touched against the nose (not possible in the average mature newborn).

The fingers of many children with Down syndrome are short and thick, and the little

finger is often curved inward. There may be a wide space between the first and second

toes and between the first and second fingers. The palm of the hand shows a peculiar

crease (a simian line), which is a single horizontal palm crease rather than the usual three

creases in the palm .

Children with Down syndrome are usually cognitively challenged to some degree.

The challenge can range from an intelligence quotient (IQ) of 50 to 70 to a child who is

profoundly affected (IQ less than 20). The extent of the cognitive

challenge is not evident at birth. The fact that the brain is not developing well is

evidenced by a head size that is usually smaller than the 10th or 20th percentile at well-

child health care visits.

These children also appear to have altered immune function as they are prone to

upper respiratory tract infections. Congenital heart disease, especially atrioventricular

defects, is common. Stenosis or atresia of the duodenum, strabismus, and cataract

disorders are also common. For as yet undetected reasons, acute lymphocytic leukemia

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occurs approximately 20 times more frequently in children with Down syndrome than in

the general population. Even if children are born without an accompanying disorder such

as heart disease, their lifespan usually is only 50 to 60 years, because aging seems to

occur faster than normal.

It’s important for children with Down syndrome to be enrolled in early educational

and play programs . Because they are prone to infections, sensible precautions such as

using good handwashing technique are important when caring for them. The enlarged

tongue may interfere with swallowing and cause choking unless the child is fed slowly.

As their neck may not be fully stable, a radiograph

to ensure stability is recommended before they engage in strenuous activities such as

competitive sports. As with all newborns, these infants need physical examination at birth

to enable detection of the genetic disorder and initiation of

parental counseling and support.

CHILDHOOD TUMORS

A number of cancers in children are also associated with chromosomal

aberrations. Chief among these are retinoblastoma (chromosome 13), Wilms’ tumor

(chromosome 11) and neuroblastoma (chromosome 1 or 11). Common non disjunction

genetic disorders include Down syndrome (trisomy 21), trisomy 13, trisomy 18, Turner

syndrome, and Klinefelter syndrome. Most of these syndromes include some degree of

cognitive challenge.

CONCLUSION:

So far we have discussed genetics definition, genes of inheritance, genetic testing,

genetic counseling, chromosomal abnormalities.

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