MENNONITE COLLEGE OF NURSING

AT

ILLINOIS STATE UNIVERSITY

Pathophysiologic Basis of Health Deviation 437

 

Genetics

 

Why discuss genetics?

 

Genetic timeline

·         1866:  Mendel wrote of his work with peas in Experiments on Plant Hybridization

·         1902:  “Sutton-Boveri chromosome hypothesis" attempted to establish a parallel between cytological chromosome behavior and the principles followed by Mendelian factors.

·         1953:  A scientific paper by James Watson and Francis Crick presented the structure of the DNA-helix

·         1976:  Oncogenes were discovered in normal DNA. The src oncogene was found in normal chicken DNA, showing that oncogenes do not have to come from outside the cell via a virus. This experiment suggested that a normal gene already present in the cell has the potential of becoming an oncogene.

·         1989:  Cystic fibrosis gene cloned by Francis S. Collins, MD, PhD (Director of the National Institute for Human Genome Research), John R. Riordan, PhD (Research Scientist, Mayo Clinic, Scottsdale), and Lap-Chee Tsui, PhD (Research Scientist with the Department of Genetics at the Research Institute of The Hospital for Sick Children, Toronto)

·         2000-J. Craig Venter, president of Celera Genomics, led mapping of human genome.

o   Basis of gene therapy—inserting normal genes into someone who has a particular disease.  Uses recombinant DNA, which takes retrovirus and removes most of the retroviral genes.  Replaces retroviral genes with therapeutic human gene.

 

 

Role of U.S. Genetics Nurses in Advanced Practice

Source:  Lea, DH, Williams, JK, Cooksey, JA, Flanagan, PA, Forte, G, & Blitzer, MG (2006) U.S. genetics nurses in advanced practice. Journal of Nursing Scholarship,38:3, 213-218.

 

“Healthcare providers who specialize in genetics health care are necessary for leading innovation and integrating new genomic knowledge into healthcare research, education, and practice.” (p.213).

 

Primary clinical area of practice:  26% genetics, 22% oncology, 13% pediatric/neonatal, 8% women’s health/OB-GYN/maternal child health, 8% adult/med surg/gerontological, 7% family, and 15% “other”

 

Types of Services provided:

·         Provide information on genetics

·         Construct pedigree and family history analysis

·         Psychosocial counseling or support to clients/family

·         Genetic counseling (including explaining risk assessment and genetic testing)

·         Case coordination or case management

·         Physical exam or assessment

·         Care for patients in clinical trials or on therapeutics

 

Basics of Genetics/Genomics

Genetics:  the study of genes and their role in inheritance; the way certain traits or conditions are passed down from one generation to another.

 

Genomics:  the study of all of a person’s genes including interactions of those genes with each other and the person’s environment.

 

Two types of cells

Gametes: 

 

Somatic cells:

Chromosome abnormalities:

 

FISH (fluorescence in situ hybridization) is a process which vividly paints chromosomes or portions of chromosomes with fluorescent molecules.  This technique is useful for identifying chromosomal abnormalities and gene mapping.

 

Commonly used genetic terms

Genotype: what the genetic material of an individual looks like (shows cystic fibrosis, etc.)

 

Phenotype:  the observable expression of a genotype

 

Allele:  alternative forms of the genetic material, some genes have multiple alleles

 

Karyotype:  an organized picture of the chromosomes found in a cell; ordered set of chromosomes.  A karyotype can demonstrate normal chromosomes (46, XX for females, and 46, XY for males) or can point out chromosomal abnormalities such as extra or missing chromosomal material (such as trisomy 21)

·         Checks for gross abnormalities

·         Order to check for extra, missing, rearrangement of chromosomes

·         Can see nondisjunction and chromosomal abnormalities, but NOT genetic/DNA disorders (cystic fibrosis)

 

Illustration of a karyotype:

                karyotype.gif

 

 

To try karyotyping patient chromosomes, go to:

http://www.biology.arizona.edu/human_bio/activities/karyotyping/karyotyping.html

 

 

Nondisjunction:  chromosomes do not sort correctly so a cell ends up with more or less chromosomes than expected.

 

Autosomal aneuploidy

 

 

Illustration (karyotype) of Trisomy 21:

 

                                trisomy 21.gif

 

Sex chromosome aneuploidy

 

 

 

 

 

 

Deletions:  occur due to chromosome breaks. 

Illustration of a deletion:

                                        deletion.gif

·         Whether the deleted segment results in disease depends on whether the deleted segment contains essential DNA

·         What material is deleted dictates the genes that are missing and as a result the condition.

o   Different deletions will have different clinical presentations

·         Contiguous gene syndromes/microdeletions:  syndromes caused by deletions of a contiguous set of genes

o   Example:  cri-du-chat syndrome = (cat's cry) syndrome = 5p- syndrome

§  A chromosomal condition that results when a piece of chromosome 5 is missing (the end of the short (p) arm of chromosome 5) 

§  The size of the deletion varies among affected individuals; studies suggest that larger deletions tend to result in more severe intellectual disability and developmental delay than smaller deletions in people with cri-du-chat syndrome.

§  The signs and symptoms of cri-du-chat syndrome are probably related to the loss of multiple genes on the short arm of chromosome 5.

§  Infants with this condition often have a high-pitched cry that sounds like that of a cat.

§  The disorder is characterized by intellectual disability and delayed development, distinctive facial features, small head size (microcephaly), low birth weight, and weak muscle tone (hypotonia) in infancy. Some are also born with a heart defect.

§  Occurs in an estimated 1 in 20,000 to 50,000 newborns

§  Slightly more common in females.

 

Source:  http://ghr.nlm.nih.gov/condition=criduchatsyndrome

 

o   Example of microdeletion:  Williams syndrome

 

 

Duplications:  the presence of an extra segment of a chromosome.  Usually more common and less harmful than deletions. 

 

Illustration of duplication:

                                              duplication.gif

 

Example:  Charcot-Marie-Tooth disease

·         Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders

·         Affects approximately 1 in 2,500 people in the United States

·         Disease named for the three physicians who first identified it in 1886 - Jean-Martin Charcot and Pierre Marie in Paris, France, and Howard Henry Tooth in Cambridge, England.

·         CMT, also known as hereditary motor and sensory neuropathy (HMSN) or peroneal muscular atrophy, comprises a group of disorders that affect peripheral nerves (peripheral neuropathies).

·         Affects both motor and sensory nerves.

o   A typical feature includes weakness of the foot and lower leg muscles, which may result in foot drop and a high-stepped gait with frequent tripping or falls.

o   Foot deformities, such as high arches and hammertoes are also characteristic due to weakness of the small muscles in the feet.

o   The lower legs may take on an "inverted champagne bottle" appearance due to the loss of muscle bulk.

o   Later in the disease, weakness and muscle atrophy may occur in the hands, resulting in difficulty with fine motor skills.

·         Onset of symptoms is most often in adolescence or early adulthood, however presentation may be delayed until mid-adulthood.

·         The severity of symptoms is quite variable in different patients and even among family members with the disease.

·         Progression of symptoms is gradual. Pain can range from mild to severe, and some patients may need to rely on foot or leg braces or other orthopedic devices to maintain mobility. Although in rare cases patients may have respiratory muscle weakness, CMT is not considered a fatal disease and people with most forms of CMT have a normal life expectancy.

Source:  http://www.ninds.nih.gov/disorders/charcot_marie_tooth

 

 

 

Translocations:  the exchange of chromosomal material between two or more chromosomes

 

Illustration of translocation:

 

           translocation.gif

 

·         If no essential chromosomal material is lost and no genes are damaged by the breakage on reunion, this person is said to have a balanced translocation and therefore will usually show no adverse phenotype

·         However, this person is at risk for producing unbalanced gametes, and therefore genetically unbalanced offspring

o   Unbalanced:  duplication/deletion, trisomy/monosomy of some genes

 

 

DNA Mutations:  any inherited alteration of genetic material (includes chromosome aberrations that cause congenital defects).  Mutations of the DNA can occur in several ways:

·         Spontaneous mutations

·         Mutations caused by mutagens

o   Chemicals

o   Viruses

o   Radiation

·         Examples of mutations:

o   Sickle cell anemia

o   Cystic fibrosis

 

Inheritance: is the transmission of  traits or diseases from parent to offspring via the genes.

 

Types of disease inheritance:

·         Autosomal recessive disease

o   The gene for the disease lies on a numbered chromosome (not a sex chromosome)

o   2 abnormal versions of a gene are necessary for the disease to occur

§  Having 1 abnormal version of the gene (known as a carrier) does not lead to the trait.

·         Carriers are usually healthy

§  2 carriers have a 25% chance of having an affected child with each pregnancy

autosomal recessive.jpg

 

o   Examples: 

§  Cystic fibrosis

§  Phenylketonuria (PKU)

§  Sickle cell disease

§  Tay-Sachs disease

§  Wilson’s disease

 

·         Autosomal dominant disease

o   The gene for the disease lies on a numbered chromosome (not a sex chromosome)

o   Only 1 abnormal version of the gene is necessary for the disease to occur

§  So…there are no carriers

§  One parent with an abnormal dominant gene has a 50% chance of having an affected child with each pregnancy

 

                              AutoDominant.jpg

 

o   Examples: 

§  Osteogenesis imperfecta

§  von Willebrand’s disease

o   May have reduced penetrance/variable expressivity

penetrance and expressivity.gif

 

 

·         X-linked recessive disease

o   The gene for the trait lies on the X chromosome (sex chromosome)

o   One abnormal version of a gene causes the trait in males (XY)

o   Females (XX) can have one normal and one abnormal version (=carrier) and will usually be healthy

o   If the female is a carrier and the male is unaffected, there is a 50% chance with each male pregnancy to have an affected son.

 

                   xlinkrecessive.jpg

 

o   Examples:

·       Bruton-type agammaglobulinemia

·       Classic hemophilia

·       Color blindness

·      Duchenne-type muscular dystrophy

 

 

Concordance:  the probability that a pair of individuals will both have a certain characteristic, given that one of the pair has the characteristic.  In twin studies, the twins are concordant when both have  or both lack a given trait.  High concordance rates for MZ* twins indicates high probability of the condition being genetic-related.  If concordance rate is <100%, there are also important environmental effects which impact on the outcome.

 

MZ  = Monozygotic twins (embryo cleaves early in development, leading to exact copies).  Share 100% of genes.  Have identical DNA.

 

DZ = Dizygotic twins (from double ovulation and fertilized by two different sperm).  Share 50% of genes.

 

Examples of Twin Studies/Concordance Rates

 

Schizophrenia

 

Prevalence in general populations

1%

 

 

Prevalence among relatives:

One affected parent or sibling

10%

Affected parent plus sibling

16%

Two affected parents

40%

2nd degree relatives

2-4%

 

 

Twin studies:

MZ twin concordance

47%

DZ twin concordance

12%

 

 

Adoption study:

adopted offspring of affected mothers

8%

adopted offspring of healthy controls

1%

 

Alcoholism

 

Twin studies:

MZ twin concordance

>60%

DZ twin concordance

<30%

 

 

Adoption study:

Adopted offspring of normal parents

5%

Adopted offspring of alcoholic parents

20%

 

 

 

 

 

Implications of Genetics for Patient Care

·         Carrier screening for those with a family history of a recessive condition

 

·         Presymptomatic diagnosis for those with a family history of a condition (for example, Huntington’s chorea)

o   Question:  Do you want to know what you have ahead of time, if there is no treatment for the condition?

 

·         Prenatal diagnosis for the unborn at risk of inheriting a genetic condition due to family history, known carrier parents, an affected parent(s), or sibling with the condition and for older mothers at increased risk of having child with chromosomal abnormality

 

·         Preimplantation diagnosis for mutation carriers/affected individuals who want to be sure embryo from IVF doesn’t have condition (for example, Huntington’s chorea) prior to implantation

 

·         Susceptibility testing to test those with certain conditions when under certain conditions (for example, individuals with Factor V Leiden mutation are at increased risk of developing thrombosis when pregnant or when taking oral contraceptives or hormone replacement therapy)

 

·         Cancer cell characterization:  3 main types of cancer from a geneticist point of view.  (taken from http://cancergenetics.wordpress.com/2007/08/01/characteristics-of-hereditary-familial-and-sporadic-cancer-syndromes/)

o   Hereditary Cancer type

§  Apparently autosomal dominant transmission of specific cancer types

§  Earlier age of onset of cancers than is typical

§  Multiple primary cancers in an individual

§  Clustering of rare cancers

§  Bilateral or multifocal cancers

§  First degree relatives of mutation carriers are at 50% risk to have the same mutation

§  Incomplete penetrance and variable expressivity, such that carriers of the family mutation may be cancer-free and the age of diagnosis of cancer among relatives will vary

§  Those who do not have the familial mutation have the general population risk for cancer

§  Example of testing:  BRCA1 and BRCA2 (inheriting one mutated BRCA1/BRCA2 predisposes to breast and ovarian cancer)

 

o   Familial Cancer type

§  More cases of a specific type(s) of cancer within a family than statistically expected, but no specific pattern of inheritance

§  Age of onset variable

§  May result from chance clustering of sporadic cases

§  May result from common genetic background, similar environment and/or lifestyle factors

§  Does not usually exhibit classical features of hereditary cancer syndromes

 

o   Sporadic Cancers type

§  Cancers in the family are likely due to nonhereditary causes

§  Typical age of onset

§  Even if there is more than one case in the family, there is no particular pattern of inheritance

§  Very low likelihood that genetic susceptibility testing will reveal a mutation

 

·         Targeted interventions

o   Genetic treatments

§  Gleevec used in CML patients.  Drug targets the abnormal protein made in cells with a Philadelphia chromosome (translocation between chromosomes 9 and 22)

§  Herceptin used in breast cancer patients:  binds to Her2 cell surface receptors to halt cell division in cancer cells where Her2 is overexpressed.

o   Pharmacogenetics:  deals with the variability of individuals’ responses to medications due to genetic variation.

o   Goal:  create an individualized drug therapy program, thereby allowing for the best choice and dose of drugs.

§  Example:  genetic testing for certain genes (such as CYP2C9) that affect the metabolism of warfarin can now be done to guide warfarin dosage and management

§  Example:  Genetic factors may influence why one approach to smoking cessation works for some smokers but not for others:

·         Smokers with 2 copies of the Ins C variant (homozygous) of the dopamine D2 receptor gene responded better to Zyban while those with the Del C variant of this gene responded better to nicotine replacement therapies such as a patch or nasal spray

o   Pharmacogenomics:  looks for genetic variations that are associated with drug discovery and development

o   Leading to the development of drugs that can be tailor made for specific individuals and adapted to each person’s own genetic makeup

 

 

·         Health education includes genetic/environmental interactions

 

 

Genomic Medicine

Goals:  To provide early detection of genetic predisposition, and to offer individualized treatment.

Hypothetical case:  A 23-year-old female elects to undergo DNA testing for genes related to several diseases.  The results suggest that while she is at lower than average risk for Alzheimer disease, she is at increased risk for breast and colon cancer, as well as for coronary artery disease.  Fortunately, preventive interventions are available to help her reduce her risk of developing each of these diseases.

 

Ethical and regulatory considerations

o   Stigmatization and the Right Not to Know

o   Potential for harm through stigmatization and discrimination, particularly in employment or insurability

o   Disclosure of Genetic Information to Family Members

o   What if the patient does not want it disclosed?

o   Genetic Testing of Children

o   Should not be performed for the benefit of a family member unless the testing is necessary to prevent substantial harm to the family member

o   Genetic Testing and Health Insurance

o   In 2001, one of Britain’s largest private life insurers revealed that it had illegally used data from experimental genetic tests to evaluate some insurance applications

o   Genetic Information Nondiscrimination Act of 2008 (GINA)

§  A new federal law that protects Americans from being treated unfairly because of differences in their DNA that may affect their health. 

§  Prevents discrimination from health insurers and employers

§  Does not cover life insurance, disability insurance, and long-term care insurance

§  Signed into federal law by President Bush on May 21, 2008

§  The parts of the law relating to health insurers took effect by May 2009, and those relating to employers will take effect by November 2009.

 

 

Excellent resource for genetics information and illustrations:

National Human Genome Research Institute (www.genome.gov)