Chapter 4: Genetics and Health Applications

HUMAN GENETICS

Human genetics, as it pertains to health care, is the study of the etiology, pathogenesis, and natural history of human conditions that are influenced by genetic factors. Genetic factors extend beyond the limited view of solely distinct genetic syndromes to encompass influences on health, the occurrence of complex disorders, individual biologic responses to illness, potential treatment and medical management approaches, and strategies for prevention or cure.

This tremendous realization is apparent through the accomplishments of the Human Genome Project. This 15-year international collaborative effort was completed in 2003. One significant goal of the Human Genome Project was to identify the approximately 30,000 human genes. These advances and the associated knowledge will continue to significantly affect the delivery of health care and nursing practice. Genetic evaluations, screening, testing, guided treatment, family counseling, and related legal, ethical, and psychosocial issues will become daily practice for nurses

The impact of genetics on nursing is significant. In 1997, the American Nurses Association (ANA) officially recognized genetics as a nursing specialty. This effort was spearheaded by the International Society of Nurses in Genetics (ISONG), which also initiated credentialing for the Advanced Practice Nurse in Genetics and the Genetics Clinical Nurse. ANA and ISONG have collaborated in the establishment of Scope and Standards of Practice for nurses in genetics practice. The purpose of this chapter is to provide the nurse with practical information, resources, representative examples, and professional considerations critical to integration of genetics knowledge into nursing practice.

UNDERLYING PRINCIPLES

Biologic and Genetic Principles

Cell: The Basic Unit of Biology

• Cytoplasm—contains functional structures important to cellular functioning, including mitochondria, which contain extranuclear DNA important to mitochondrial functioning.
• Nucleus—contains 46 chromosomes in each somatic (body) cell, or 23 chromosomes in each germ cell (egg or sperm) (see Figure 4-1, page 34).

FIGURE 4-1 Cells, chromosomes, DNA, and genes.

Chromosomes

• Each somatic cell with a nucleus has 22 pairs of autosomes (the same in both sexes) and 1 pair of sex chromosomes.
• Females have two X sex chromosomes; males have one Y sex chromosome and one X sex chromosome.
• Normally, at conception, each individual receives one copy of each chromosome from the maternal egg cell and one copy of each chromosome from the paternal sperm cell, for a total of 46 chromosomes.
• Karyotype is the term used to define the chromosomal complement of an individual, for example, 46, XY, as is determined by laboratory chromosome analysis.
• Each chromosome contains about 2,000 genes.

Genes

• The basic unit of inherited information.
• Each human nucleated somatic cell has about 30,000 genes in the nucleus. Cells also have some non-nuclear genes located within the mitochondria within the cytoplasm.
• Alternate forms of a gene are termed alleles.
• For each gene, an individual receives one allele from each parent, and thus has two alleles for each gene on the autosomes and also on the X chromosomes in females.
• Males have only one X chromosome and therefore have only one allele for all genes on the X chromosome; they are hemizygous for all X-linked genes.
• At any autosomal locus, or gene site, an individual can have two identical alleles (homozygous) for that locus or can have two different alleles (heterozygous) at a particular locus; for example, for eye color.
• Genotype refers to the constitution of the genetic material of an individual; for practical purposes it is commonly used to address a specific gene pair. For example, the gene for sickle cell disease, the gene for cystic fibrosis, or the gene for familial polyposis.
• Phenotype refers to the physical or biochemical characteristics an individual manifests regarding expression of

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  the presence of a particular feature, or set of features, associated with a particular genes.
• Each gene is composed of a unique sequence of DNA bases.

DNA: Nuclear and Mitochondrial

• Human DNA is a double-stranded helical structure comprised of four different bases, the sequence of which codes for the assembly of amino acids to make a protein—for example, an enzyme. These proteins are important for the following reasons:
  • For body characteristics such as eye color
  • For biochemical processes such as the gene for the enzyme that digests phenylalanine
  • For body structure such as a collagen gene important to bone formation
  • For cellular functioning such as genes associated with the cell cycle
• The four DNA bases are adenine, guanine, cytosine, and thymine-A, G, C, and T.
• A change, or mutation, in the coding sequence, such as a duplicated or deleted region, or even a change in only one base, can alter the production or functioning of the gene or gene product, thus affecting cellular processes, growth and development.
• DNA analysis can be done on almost any body tissue (blood, muscle, skin) using molecular techniques (not visible under a microscope) for mutation analysis of a specific gene with a known sequence or for DNA linkage of genetic markers associated with a particular gene.

Normal Cell Division

• Mitosis occurs in all somatic cells, which under normal circumstances results in the formation of cells identical to the original cell with the same 46 chromosomes.
• Meiosis, or reduction division, occurs in the germ cell line, resulting in gametes (egg and sperm cells) with only 23 chromosomes, one representative of each chromosome pair.
• During the process of meiosis, parental homologous chromosomes (from the same pair) pair and undergo exchanges of genetic material, resulting in recombinations of alleles on a chromosome and thus variation in individuals from generation to generation.

GENETIC DISORDERS

Presentations warranting genetic consideration include mental retardation, birth defects, biochemical or metabolic disorders, structural abnormalities, multiple miscarriages, and family history of the same or related disorder.

Disorders that result from abnormalities of chromosomes or genes or that are, at least in part, influenced by genetic factors are described in Table 4-1.

TABLE 4-1 Selected Genetic Disorders

DISORDER AND INCIDENCE CHARACTERISTICS ETIOLOGY AND RECURRENCE RISKS CONSIDERATIONS AND COMMENTS Chromosomal Disorders Autosomal Down syndrome (Trisomy 21) 1 in 700 neonates; incidence increases with advanced maternal age (eg, risk at maternal age 25 is 1 in 1350; at age 35, 1 in 384; at age 45, 1 in 28) Brachycephaly: oblique palpebral fissures; epicanthal folds; Brushfield spots; flat nasal bridge; protruding tongue; small, low-set ears; clinodactyly; simian crease; congenital heart defects; hypotonia; mental retardation; growth retardation; dry, scaly skin; increased risk for childhood leukemia and early onset Alzheimer's disease Extra copy of number 21 chromosome (total of three copies): 94%—trisomy Down syn-drome (karyotype 47, +21)—three distinct number 21 chromosomes due to nondisjunction (failure of chromosomal separation during meiosis); recurrence risk 1%, plus maternal age- related risk if over 35 4% —translocation Down syndrome—extra number 21 attached to another chromosome, usually a number 13 or number 14; half of these translocations are new occurrences, the other half are inherited from a parent. 2% —mosaic Down synd- rome—affected has two different cell lines, one with the normal number of chromosomes and the other cell line trisomic for the number 21 chromosome; due to a postconception error in chromosomal division during mitosis. Recurrence risk for parents of affected are dependent on one or more of the following: chromosomal type of disorder, maternal age, parental karyotype, family history, and sex of transmitting parent and other chromosome involved (if translocation). May demonstrate nuccal thickening prenatally on ultrasound examination. Associated with moderate mental retardation. No phenotypic differences between trisomy Down syndrome and translocation Down syndrome. Chromosome analysis should be performed on all persons with Down syndrome. Prenatal maternal serum screening can adjust risk for the pregnancy. Trisomy 13 (Patau syndrome) 1 in 5,000 live births Holoprosencephaly; cleft lip or palate, or both; abnormal helices; cardiac defects; rocker- bottom feet; overlapping positioning of fingers; seizures; severe mental retardation Extra number 13 chromosome (total of three copies): Either trisomy form, due to nondisjunction, with less than a 1% recurrence risk; or translocation form, with recurrence risk less than that of translocation Down syndrome and dependent on other factors, including chromosomes involved. 44% die within the first month; 18% survive first year of life. Trisomy 18 (Edwards syndrome) 1 in 6,000 live births Small for gestational age (may be detected prenatally); feeble fetal activity; weak cry; prominent occiput; low-set, malformed ears; short palpebral fissures; small oral opening; overlapping positioning of fingers (fifth digit over fourth, index over third); nail hypoplasia, short hallux; cardiac defects; inguinal or umbilical hernia; cryptorchidism in males; severe mental retardation Extra number 18 chromosome (total of three copies): Majority due to trisomy with less than 1% recurrence risk. Most trisomy 18 conceptions miscarry; 90% die within first year of life. Sex Chromosome Klinefelter syndrome 1 in 700 males; 47, XXY abnormality in 90%; other 10% have more than two X chromosomes in addition to the Y chromosome or have mosaicism (about 20%) Body habitus may be tall, slim, and underweight; long limbs; gynecomastia; small testes; inadequate virilization; azoospermia or low sperm count; cognitive defects; behavioral problems Due to nondisjunction during meiosis, except for cases of mosaicism, which are due to mitotic nondisjunction. No distinguishing features prenatally. Diagnosis may not be suspected or pursued before puberty. Diagnosis in childhood is beneficial in planning for testosterone replacement therapy, in addition to accurate understanding of learning or behavioral problems. Tend to be delayed in onset of speech, have difficulty in expressive language; may be relatively immature; may have history of recurrent respiratory infections. Turner syndrome (45, X) 1 in 2,500 female births Webbing of neck and short stature: lymphedema of hands and feet as neonate; congenital cardiac defects (especially coarctation of the aorta); low posterior hairline; cubitus valgus; widely spaced nipples; underdeveloped breasts; immature internal genitalia (eg, streak ovaries); primary amenorrhea; learning disabilities About 50% due to a nondisjunctional error during meiosis (karyotype 45, X); 20% are mosaic due to nondisjunction during mitosis; 30% have two X chromosomes but one is functionally inadequate (eg, due to presence of abnormal gene); generally a sporadic occurrence. Webbing of neck and short stature may be detected prenatally by ultrasound. Early diagnosis enhances optimal health care management, eg, planning for administration of growth hormone therapy, estrogen replacement. Psychosocial implications associated with short stature, delayed onset of puberty. Infertility associated with ovarian dysgenesis; oocyte donation and adoption are generally the only options for having children. Microdeletion/Microduplication Fragile X 1 in 1,200 males; 1 in 2,500 females Motor delays; hypotonia; speech delay and language difficulty; hyperactivity; classic features including long face, prominent ears, and macroorchidism manifest around puberty; autism (about 7% of males); mental retardation in most males; learning disabilities in most affected females Mutation in the fragile X mental retardation gene (FMR-1), represented as a large DNA expansion of a normally present trinucleotide. Carrier mother of an affected male has a 50% risk for future affected males and 50% chance of transmitting the FMR-1 X chromosome to a daughter who would be a carrier, may be unaffected, or manifest features associated with the fragile X syndrome and has a 50% chance of transmitting that gene to future offspring. Both cytogenetic testing for expression of the fragile X site and DNA analysis for the expansion are available, but the latter is superior. Testing for methylation status of the DNA increases sensitivity. Phenotypic expression of this gene in males and females is variable; genetic mechanisms determining expression of this gene are very complicated. Fragile X should be considered in the differential diagnosis of any mentally retarded male who is undiagnosed; it is the most common mental retardation in males. Prader-Willi syndrome Estimated incidence 1 in 25,000 Hypotonia and poor sucking ability in infancy; almond-shaped palpebral fissures; small stature; small, slow growth of hands or feet; small penis, cryptorchidism; insatiable appetite, behavioral problems developing in childhood; below-normal intelligence or mental retardation Cytogenetic microdeletion in chromosome 15 q11 to 13 identified in 50% to 70% of cases; deletion associated with paternally inherited number 15 chromosome. Generally sporadic occurrence; empiric recurrence risk 1.6%. Consider diagnosis in infants presenting with hypotonia and sucking problems where etiology is unknown. Associated with lack of a functioning paternal gene at this locus; presents clinical evidence for the necessity of two functioning genes, both a maternal and paternal contribution. Another distinct entity, termed Angelman syndrome, is associated with a deletion of the maternal contribution in this same cytogenetic region; it is also associated with mental deficiency, but with a different phenotypic presentation. Mendelian Disorders — Single Gene Autosomal Dominant Achondroplasia 1 in 10,000 live births Increased incidence associated with advanced paternal age (> 40) Megalocephaly; small foramen magnum and short cranial base with early spheno-occipital closure; prominent forehead; low nasal bridge; midfacial hypoplasia; small stature; short extremities; lumbar lordosis; short tubular bones; incomplete extension at the elbow; normal intelligence Autosomal dominant inheritance; 80% to 90% are due to a new mutation and neither parent is affected. An affected parent has a 50% risk to transmit the gene to each child. Hydrocephalus can be a complication of achondroplasia and may be masked by megalocephaly. Risk for apnea secondary to cervical spinal cord and lower brain stem compression due to alterations in shape of cervical vertebral bodies; respiratory problems are also a risk because of the small chest and upper airway obstruction. Can be diagnosed prenatally by ultrasound. Osteogenesis imperfecta (Type 1) 1 in 15,000 live births Blue sclerae; fractures (variable number); deafness may occur Defect in the procollagen gene associated with decreased synthesis of a constituent chain important to collagen structure. Can occur as a new mutation in that gene or can be inherited from a parent who has a 50% recurrence risk to transmit the gene; most severe cases represent a sporadic occurrence within a family. There are at least four general classifications of osteogenesis imperfecta, each with varying clinical severity, presentation, and pattern of genetic transmission. Treatment with calcitonin and fluoride may be beneficial in reducing the number of fractures. Breast and breast/ovarian cancer syndrome Accounts for 5% to 10% of breast cancer Breast cancer (usually, but not exclusively, early-age onset, premenopausal); ovarian cancer Mutation in the BRCA-1 or BRCA-2 gene; poses increased susceptibility (not certainty) for breast (56% to 87%) and/or ovarian (16% to 60%) cancer. Studies have also noted increased risk for prostate cancer, colon cancer in some families; also an association between male breast cancer and BRCA-2 mutations. Familial adenomatous polyposis (FAP) Accounts for about 1% of colon cancer Associated with multiple adenomatous colorectal polyps (classic: > 100; atypical: < 100), desmoid tumors, other GI polyps, jaw cysts; family history of polyps or colorectal cancer; polyps progress to cancer; polyps can be present in childhood Mutations in the APC gene (a tumor suppressor gene). The majority of mutations result in a truncated protein. Genetic testing (protein truncation testing is available). If mutation is identified in affected person, relatives can be tested for the same finding. Relatives at risk, whether by family history or by genetic testing, should start cancer screening by age 18, if not earlier, if there are symptoms or as a baseline. Screening includes colonoscopy, ophthalmologic examination. Autosomal Recessive Sickle cell disease 1 in 400 live births of African American ancestry Physically normal in appearance at birth; hemolytic anemia and the occurrence of acute exacerbations (crises), resulting in increased susceptibility to infection and vascular occlusive episodes Point mutation in the sickle cell gene resulting in an altered gene product; red blood cells susceptible to sickling at times of low oxygen tension. Parents of an affected individual are both unaffected carriers of one abnormal copy of the sickle cell gene (sickle cell trait) and together have a 25% risk for recurrence in any offspring. 1 in 10 African Americans is a carrier of the sickle cell gene; population screening is indicated for these individuals. Unaffected siblings of an affected individual have a two-thirds, or 67%, risk to have the sickle cell trait and should be screened. See page 1633 for nursing care. Prenatal testing is available through DNA analysis from specimen obtained during chorionic villus sampling or amniocentesis. Cystic fibrosis (CF) 1 in 2,000 live births (predominantly White) Phenotypically normal at birth; may present with meconium ileus (10%) as neonate or later with persistent cough, recurrent respiratory problems, gastrointestinal complaints, malnutrition, abdominal pain, or infertility Mutation in the cystic fibrosis transmembrane conduction regulator gene on chromosome 7 results in an abnormality of a protein integral to the cell membrane. Parents of an affected individual are both considered obligate carriers of one copy of the abnormal CF gene; thus, together they have a 25% recurrence risk with each conception. 1 in 20 whites is a carrier of a CF gene mutation. Several different mutations have been identified within the CF gene, the most common of which is DF508, which accounts for about 70% of CF mutations. CF screening can identify about 85% of all CF mutations (95% in Jewish population); it is not yet being used for general population screening. DNA analysis of the CF gene is advised for affected individuals and relatives of persons with CF. See page 1452 for nursing care. Tay-Sachs disease 1 in 3,600 Ashkenazic Jews Normal at birth; progressive neurodegenerative manifestations, including loss of developmental milestones and lack of central nervous system (CNS) maturation; cherry-red spot on macula Mutation in the gene for hexosaminidase A, an enzyme important to cellular metabolic processes, results in accumulation of metabolic by-products within the cell (especially brain), impairing functioning and causing the neurodegenerative effects. Parents of an affected individual are both considered unaffected obligate carriers of one copy of the Tay-Sachs disease gene; together they have a 25% risk of recurrence in their offspring. About 1 in 25 Ashkenazic Jews is a carrier of the Tay-Sachs gene; about 1 in 17 French Canadians is a carrier of an abnormal Tay-Sachs gene (different mutation from that of the Jewish ancestry); persons of these ancestries should be screened. No treatment available; results in death in childhood. Prenatal and preimplantation testing are available. X-Linked Recessive Duchenne's muscular dystrophy (DMD) 1 in 3,500 males Phenotypically normal at birth; dramatically elevated creatinine kinase level (detectable as early as age 2 days); hypertrophy of the calves; history of tendency to trip and fall (at about age 3 years); Gowers' sign (tendency to push off oneself when getting up from a sitting position) DNA mutation, generally a deletion, detectable in 70% of affected males. Carrier females have a 25% risk with each pregnancy to have an affected male, a 25% risk to have a carrier female, a 25% chance to have a healthy male, and a 25% chance to have a healthy noncarrier female. 1 in 1,750 females is a carrier of the DMD gene. In the case of an isolated affected male, the mother has a two-thirds statistical risk that she is a carrier of the DMD gene and a one-third chance that her affected son arose as the result of a new mutation in that gene (she is not a carrier). DNA testing is recommended for affected males, and once type of gene mutation is known in that family, prenatal diagnosis and evaluation of potential female carriers can be carried out. DNA analysis may provide clues as to expected clinical severity. Hemophilia A 1 in 7,000 males Phenotypically normal at birth; bleeding tendency (ranging from frequent spontaneous bleeds associated with the severe form to bleeding only after trauma associated with the mild form) Deficiency of Factor VIII (antihemophilic factor) due to abnormality in this gene located on the X chromosome. Carrier females have a 25% risk with each pregnancy to have an affected son, a 25% risk for a carrier daughter, and a 25% chance each for a healthy unaffected daughter or son. Mates of affected males should be tested for carrier status. If the female is not a carrier, the affected male will not have any affected children. Frequency of carrier females is about 1 in 3,500. The severe form occurs in about 48% of cases. Moderate cases account for 31% The mild form accounts for 21% of cases. See page 1641 for nursing care. Glucose 6-phosphate dehydrogenase (G6PD) 10% to 14% of male live births of African American origin Phenotypically normal at birth; many remain asymptomatic through life; may manifest acute hemolysis associated with exposure to outside factors, eg, certain medications Abnormality of the G6PD gene on the X chromosome. Carrier females have a 25% risk with each pregnancy to have an affected male and 25% risk to have a carrier female. Be aware of drugs, such as anti malarial drugs or sulfona mides; or chemicals, such as phenylhydrazine (used in silvering mirrors, photography, soldering) associated with hemolysis in G6PD-deficient individuals. Multifactorial Disorders Neural tube defects 1 in 1,000 live births Abnormalities of neural tube closure, ranging from anencephaly to myelomeningocele to spina bifida occulta Probably several genetic factors may predispose certain individuals or families, to susceptibility, but certain environmental (eg, prolonged hyperthermia) and other unknown factors play an additive rule in surpassing an arbitrary threshold, placing the developing fetus at risk. Recurrence risk for isolated neural tube defects range between 1% and 5%. Recurrence risk for isolated neural tube defects is dependent on the severity of the defect, ie, a defect in the neurulation (the cranial end of the neural tube) versus cannulation (the development of the caudal end) and if there is a positive family history. Maternal screening can be performed prenatally (after 14 weeks' gestation) through alpha-fetoprotein levels in maternal serum. Can be associated with chromosomal or genetic disorders. Cleft lip and/or cleft palate 1 in 1,000 live births Unilateral or bilateral; cleft lip and cleft palate may occur together or in isolation Failure of migration and fusion of the maxillary processes during embryogenesis. Recurrence risk for first-degree relatives of a person with an isolated cleft lip or cleft palate ranges between 2% and 6%. Clefting can occur as an isolated congenital abnormality or be one component of a syndrome, genetic defect, or chromosome abnormality, these latter three of which are associated with a recurrence risk specific to that disorder. Recurrence for isolated cleft lip or palate are dependent on the type of cleft, the sex of the affected individual, and the family history.

Classification of Genetic Alterations

Chromosomal

• The entire chromosome or only part can be affected. This is usually associated with birth defects and mental retardation because there are extra or missing copies of all genes associated with the involved chromosome.
  • Numerical—abnormal number of chromosomes due to nondisjunction (error in chromosomal separation during cell division). Examples are Down and Klinefelter syndromes.
  • Structural—abnormality involving deletions, additions, or translocations (rearrangements) of parts of chromosomes. Examples are Prader-Willi and Angelman syndromes.
  • Fragile sites—regions susceptible to chromosomal breakage such as in fragile X syndrome.
• May involve autosomes or sex chromosomes.

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Single Gene or Pair of Genes

• Manifestations are specific to cells, organs, or body systems affected by that gene.
• Autosomal dominant—presence of a single copy of an abnormal gene results in phenotypic expression.
  • These genes may involve proteins of a structural nature such as collagen. Affected individuals are usually of normal intelligence.
  • Can be inherited from one parent, whose physical manifestations can vary, depending on the specific disorder and the gene's penetrance and expressivity; for example, neurofibromatosis.
  • An individual with an autosomal dominant gene has a 50% chance of transmitting that gene to all offspring.
• Autosomal recessive—requires that both alleles at a gene locus be abnormal for an individual to be affected.
  • These genes are frequently important to biochemical functions, such as the break down of phenylalanine. Depending upon the gene and the nature of the mutation, affected individuals may be of normal intelligence or be mentally retarded.
  • Generally, both parents of an affected child are considered obligate carriers (unaffected) of one copy of the abnormal gene.
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  • Such a carrier couple has a 25% chance, with each pregnancy, to have an affected child, a 50% chance for the child to be an unaffected carrier, and a 25% chance for the child to be an unaffected noncarrier.
• X-linked recessive—due to one or more abnormal genes on the X chromosome.
  • These genes may be important to structure or biochemical function. Depending upon the gene and the nature of the mutation, affected individuals may be of normal intelligence or be mentally retarded.
  • Recessively inherited, in most cases, meaning that two abnormal genes are required to be affected. However, only one abnormal gene needs to be present for a male to be affected because males are hemizygous for all X-linked genes, as in Duchenne muscular dystrophy.
  • Females are typically only carriers of X-linked recessive disorders because the presence of a corresponding normal gene on the other X chromosome in a female produces enough gene product for normal functioning; females can be affected to varying degrees in certain circumstances.
  • A carrier female has a 25% chance, with each pregnancy, to have an affected son, a 25% chance to have a carrier daughter, a 25% chance to have an unaffected son, and a 25% chance to have an unaffected noncarrier daughter.
  • A male with an abnormal X-linked gene who has children will transmit that gene to all of his daughters, who will be carriers of that gene (usually unaffected); none of his sons will inherit his abnormal X-linked gene because they receive his Y chromosome.
• X-linked dominant—relatively rare.
  • Mutations in these genes are usually lethal to male conceptions, as in Rett syndrome.
  • Depending upon the gene and the nature of the mutation, affected females may be of normal intelligence or be mentally retarded. An example is incontinentia pigmenti.
• Mitochondrial—genes whose DNA is within the mitochondria, which are located in the cytoplasm, not in the nucleus, and therefore do not follow Mendelian laws of inheritance.
  • Many of these genes are associated with respiratory functions within mitochondria and thus affect energy capacity of cells. Disorders may be manifested by diminished strength in the involved tissue, or myopathy.
  • Essentially are maternally inherited because the egg cell contains the cytoplasmic material that is involved in the zygote; the sperm cell contributes mainly only nuclear DNA.
  • Varying phenotypes, depending on the number and distribution of abnormal mitochondrial genes.
  • Can affect males or females, but males transmit few, if any, mitochondrial genes.

Multifactorial

• Caused by multiple genetic factors in addition to other nongenetic influences (eg, environmental).
• Because of the genetic components, affected individuals or close relatives are at an increased risk, compared with the general population, to have an affected child or develop the condition themselves.
• Elimination of known non-genetic risk factors or proactive treatment regimen in some conditions can reduce risk for occurrence (eg, diet modification to manage hypercholesterolemia, cessation of smoking to reduce risk of cancer, or weight control and exercise to prevent type 2 diabetes in susceptible individuals).

GENETIC COUNSELING

Genetic counseling is a communication process that deals with human problems associated with the occurrence, or recurrence, of a genetic disorder in a family or individual at increased risk for a condition that has a genetic component due to factors such as ancestral background or due to the results of screening tests. For these individuals or families, specific concern exists about risk associated with a certain problem or because of the relationship to someone who is affected (the proband). Several steps occur in the genetic evaluation, including obtaining and reviewing the medical history and records of the affected; eliciting the family history, with special attention to factors pertinent to the diagnosis in the proband; evaluating and examining the affected (if available and indicated); ordering appropriate tests and interpreting results; and then meeting with the person seeking the consultation and/or the proband.

Goals of Genetic Counseling

Assist the patient and proband to:

• Comprehend the medical facts, including the diagnosis, the possible course of the disorder, and the available management.
• Understand the inheritance of the disorder and the risk of recurrence in specified relatives.
• Understand the options for dealing with the risk of recurrence.
• Choose course of action that seems appropriate to the individuals involved; considering their risk, family goals, and religious beliefs, and act in accordance with that decision.
• Make the best possible adjustment to the disorder.
• Understand the individual risks and the types of testing available and assist with interpretation and follow-up of test results.

Identify People in Need of Genetic Assessment and Counseling

• Parents of a child with a birth defects, mental retardation, or known or possible genetic disorder
• Any individual with a genetic or potentially genetic disorder
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• People with a family history of mental retardation, birth defects, genetic disorder, or condition that tends to run in the family
• Pregnant women who will be age 35 or older at the time of delivery
• Couples of ethnic origin known to be at an increased risk for a specific genetic disorder
• Couples who have experienced two or more miscarriages
• Pregnant women who have an elevated or low maternal serum screening test result such as alpha-fetoprotein
• Women who have been exposed to drugs or infections during pregnancy
• Couples who are related to each other
• People who are concerned about the risk for a genetic disorder

Genetic Screening, Testing, and Research

Screening

• Screening is the level of testing offered to large populations (eg, neonate) or to high-risk segments of the population (such as Blacks, Ashkenazi Jews, Mediterranean peoples) to identify individuals with a genetic disorder, increased risk for abnormality, or carriers of a genetic disorder.
• Criteria include that the test itself must be reliable, appropriate to the designated population, and cost-effective and that the condition being tested for must be treatable or that early identification will enhance quality of life.
• Neonate screening varies among hospitals and states; however, all states and facilities test for disorders such as phenylketonuria and hypothyroidism, and most test for maple syrup urine disease, galactosemia, and hemoglobi nopathies.
• Prenatal screening includes maternal serum alpha-feto protein (AFP) alone or the triple screen (includes measurement of maternal serum AFP, beta-human chorionic gonadotropin, and estriol). A fourth protein, inhibin-A, is measured by some laboratories. These tests are conducted after 14 weeks' gestation and can identify pregnancies at increased risk for neural tube defects (NTD), Down syndrome, trisomy 13 (Patau syndrome), and trisomy 18 (Edwards syndrome).

Testing

• Biochemical testing is done on body tissue or fluid to measure enzyme levels and activity.
• DNA testing is done on blood or tissue samples to look for a gene mutation or to study DNA linkage.
• Chromosomal testing is done on nucleated cells (usually blood cells) or other tissue for detection of various conditions, such as extra, missing, deleted, duplicated, or rearranged chromosomes.

Prenatal Testing

• Chorionic villus sampling—for chromosomal, biochemical, and DNA testing; done at 9 to 12 weeks' gestation.
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• Amniocentesis—for chromosomal, biochemical, and DNA testing at 13 weeks' gestation (early amniocentesis); AFP can be done at 14 to 18 weeks' gestation.
• Ultrasound—for dating pregnancy and assessing fetal structures, placenta, and amniotic fluid; done throughout pregnancy, but fetal structures are best visualized after 12 weeks.
• Acetylcholinesterase in amniotic fluid for suspected NTD.
• Fetoscopy—for obtaining fetal blood samples or visualizing details of fetal structures; done during the second trimester.
• Percutaneous umbilical blood sampling—for obtaining fetal blood; done during second trimester.

Preimplantation Diagnosis

• Requires in vitro fertilization so that embryos can form in the laboratory. One or two cells are removed from the embryo and sent for genetic testing. Only embryos lacking the genetic composition for disease are placed into the womb for further development.
• Useful if the embryo is at an increased risk for a specific genetic condition; for example, an autosomal/X-linked recessive, autosomal/X-linked dominant, or chromosomal condition.

Research

• Testing is performed to further understand the genetics of a disorder or biochemical process.
• Genetic research is not clinical testing, and may have no clinical value to the patient's case.
  • Some states, such as New York, mandate that genetic research specimens must be kept anonymous and that results not be provided to an individual for any clinical use.
• There is ongoing and extensive research on cancer susceptibility genes.

Additional Genetic Testing Consideration

DNA banking—extraction and storage of one's DNA from blood through a qualified genetics laboratory—requires informed consent, proper collection, and prompt handling.

Nursing Roles and Responsibilities

• Recognize or suspect genetic disorders by their physical characteristics and clinical manifestations.
• Create a genetic pedigree (diagram of the family history), including cause of death and any genetically linked ailments (see Figure 4-2).

  FIGURE 4-2 Genetic pedigree of a patient with breast cancer. Maternal side only is shown; however, both maternal and paternal sides are assested. Genetic risk may run through either side.

• Explain those aspects of diagnosis, prognosis, and treatment that affect the patient and his family. Relate information that parents, affected or at-risk individuals, and caregivers need to know to plan for the care of the patient.
• Clear up misconceptions and allay feelings of guilt.
• Assist with the diagnostic process by exploring medical and family history information, by using physical assessment skills, by obtaining blood samples, and/or by assisting with other means of sample collection, as indicated.
• Enhance and reinforce self-image and self-worth of parents, child, or the individual at risk for or presenting with a genetic condition.
• Encourage interaction with family and friends; offer referrals, phone numbers of support groups.
• Refer and prepare family for genetic counseling.
  • Inform that prenatal testing does not mean termination of pregnancy (eg, it may confirm that the fetus is not affected, thus eliminating worry throughout pregnancy, although the determination of an abnormality is also a possibility).
  • Encourage parents and patient to allow adequate time to deliberate on a course of action (eg, they should not rush into a test without full knowledge of what the results can and can't tell, nor should they rush to make future reproductive decisions such as tubal ligation because in a few years they may want more children).
  • Remain nonjudgmental.
• Check with the state (for example, state health department) or with the American Society of Human Genetics (301-571-1825) for information and resources regarding neonate testing required, state regulations on genetic testing and research.
• Recognize that there are many ethical, legal, psychosocial, and professional issues associated with obtaining, using, and storing genetic information.
  • Be aware of associated professional responsibilities, including informed consent, documentation in medical records, medical releases, and individual privacy of information.
  • Refer to federal legislation (Health Insurance Portability and Accountability Act, 1997) that deals with protection from genetic discrimination in medical insurance; individual state legislation; genetics professional societies (see below); and the World Health Organization document on ethical considerations in genetic testing and services.