Chapter Outline
From the Genetic Age into the Genomic Age
The Diagnostic Utility of Family History Data
Types of Genetic and Genomic Tests
Carrier Screening May Reveal Asymptomatic and Symptomatic Individuals
Susceptibility and Presymptomatic Testing
Pharmacogenetic and Pharmacogenomic Testing
Clinical Decision-Making Framework for Genetic Testing
Collaborating with Genetic Health Professionals and Lifelong Learning in Genetics and Genomics
The Physician Assistant’s Role in the Genomic Age: Putting it all Together
From the Genetic Age into the Genomic Age
Continuing research advances in molecular biology, including genomic sequencing, increases in computing power, and decreases in technology, have propelled what was the genetic age into the genomic age. These research advances will fundamentally transform the practice of clinical medicine. This chapter provides an overview of some of these advances and explains their relevance for physician assistants (PAs) practicing in primary care or specialty settings. Relevant subtopics are reviewed, including the language of genetics and genomics, the molecular genetic basis of human disease, the utility of family history data in diagnosis, and a summary and description of various types of genetic and genomic testing currently in use. Finally, a clinical decision-making framework is presented to help PAs determine which clinical situations may benefit from testing; this clinical decision-making framework includes the basic tenets and ethical considerations frequently encountered in such testing situations. Mastery of the information in this chapter enables PAs to (1) use genetic and genomic terms with precision, (2) understand the clinical relevance of the molecular genetic characterization of human diseases, (3) use the diagnostic power of the family pedigree, (4) distinguish between the different types of genetic and genomic testing and when to use them, and (5) appreciate the value of establishing professional relationships with genetic health professionals.
Genetics and Genomics: The Language of Modern Medicine
Genetic and genomic advances have changed the language of medicine. The daily discourse of medicine is dotted with terms such as sequencing, polymerase chain reaction, and mutations. Therefore, understanding genetics and genomics is as important as understanding anatomy and physiology. An understanding of genetic and genomics allows an ever greater level of precision when communicating with patients, colleagues, and other professionals. For instance, the words allele and gene have been used interchangeably, but they do not represent the same concept. Although humans have approximately 22,000 genes, we also have variations of these genes. Variations or alternate forms of genes are called alleles ; thus, when referring to a variant of a gene , the word to use is allele . Similarly, the word genomic is now routinely used. What is the difference between genetic and genomic ? In general, genetic refers to a single allele or a mutation within an allele. In contrast, the term genome refers to the entirety of an organism’s genetic information. This includes the coding sequences (alleles) and the noncoding sequences—all of the nuclear DNA, mitochondrial DNA (mtDNA), and RNA. The aim of genomics is to understand the structure and function of different genomes (e.g., humans, primates, bacterial) as well as to study the interplay of different genomics in a variety of environments (see Box 15.1 ).
Allele: Different forms of a gene are called alleles. Alleles are variations in the DNA sequence of a gene. For example, A and B are specific alleles for the ABO blood group gene. Allelic variants can be conceptualized similarly to a type of biological maker, such as alpha-fetoprotein or prostate-specific antigen.
Familial clustering: When two or more biological family members have the same or a similar disorder but there is no obvious mendelian pattern of inheritance.
Genes: The fundamental unit of heredity, responsible for transmitting information from one generation to the next in gametes. The coding sequences of DNA are called genes . Genes are referred to as alleles (see Allele).
Genome: The entirety of an organism’s genetic information. This means the coding sequences (i.e., genes) and the noncoding sequences—all the nuclear DNA, mtDNA, and RNA.
Genomics: Aims to understand the structure and functioning of different genomes (e.g., human primates, invertebrates) as well as the interplay of different genomes with different environments.
Heterozygous: The alleles at a genetic locus are different from one another. An individual with blood type AB is heterozygous at the ABO blood group locus.
Homozygous: The alleles at a genetic locus are identical. For instance, an individual with blood type O (i.e., genotype OO) is homozygous for the O allele.
Locus: Genes and their alleles are located on all chromosomes, and the position each one occupies is called a locus (plural, loci). For instance, the locus for the allele for β-hemoglobin (HBB) is on chromosome 11p15.5. HBB is a component (subunit) of a larger protein called hemoglobin, which is located on the inside of red blood cells.
Mitochondrial DNA (mtDNA): Mitochondria contain an independent circular genome with 37 alleles. Mitochondria are passed from mothers to both female and male children, and this is referred to as maternal inheritance.
Multifactorial inheritance: Any type of non-mendelian inheritance including familial clustering; also referred to as complex inheritance.
Mutation: Accidental alterations or changes in our genetic material, DNA. There are three varieties of mutations: no effect, beneficial, or harmful. Most mutations are thought to have no effect on human health. These mutations generally occur in the noncoding region of our genome and are not believed to affect human health. These no effect mutations are sometimes called silent or neutral mutations. Mutations that occur in the coding region of our genome can be beneficial or harmful. Beneficial mutations confer health benefits; harmful mutations are usually associated with disease.
Polymorphism: A piece of DNA that has more than one form (allele), each of which occurs with at least 1% frequency, is said to be polymorphic ( poly, many; morph, forms). Polymorphisms are a normal part of genetic variability. Polymorphisms of the same gene may or may not have different functions.
Single nucleotide polymorphism (SNP; pronounced “snip”): A polymorphism that involves a change at a base pair of DNA (e.g., from a C to a G or an A to a T). SNPs are the most common type of genetic variation in humans. Some SNPs involve changes in the function of a protein that is made from a gene, but others are silent. Coding SNP (cSNP) is a SNP that occurs in a coding region.
A Genetic and Genomic View of Human Disease
Almost every human disease has a genetic component. Most diseases have a weak genetic component, meaning an individual may be vulnerable (susceptible) to developing a disease. Other diseases have a strong genetic component, meaning an individual has a higher likelihood of developing a disease. The relative strength or magnitude of a genetic effect for a disease can be categorized along a continuum ranging from susceptibility (multifactorial) to causative (mendelian) alleles. Although we typically consider two broad genetic classes of human disease, multifactorial and mendelian, it is more appropriate to consider the spectrum of the genetic component of human disease ( Fig. 15.1 ).
Multifactorial genetic diseases account for the majority of health problems in the population. Some examples include hypertension, asthma, coronary artery disease, osteoarthritis, and Parkinson disease. These diseases are associated with susceptibility alleles . Susceptibility means an individual is vulnerable (susceptible) to developing a disease. A susceptibility allele confers an increased risk that an individual may develop it, but the susceptibility allele is not sufficient to cause the disorder. Multifactorial genetic diseases usually do not show a recognizable mendelian inheritance pattern (i.e., autosomal recessive, autosomal dominant, or X-linked) on a family pedigree. However, sometimes two or more family members may have the same multifactorial genetic disease, which is termed familial aggregation .
Mendelian diseases are not rare, but they occur less frequently than multifactorial genetic diseases. Examples include hypercholesterolemia, cystic fibrosis (CF), and sickle cell disease (SCD). In these diseases, a mutation in one or more alleles is directly associated with the disease, so the term causative allele is used. Mendelian diseases typically exhibit a distinct pattern of inheritance (e.g., autosomal dominant, autosomal recessive, X-linked).
Molecular Genetic Characterization of Human Disease
Human diseases are now being classified according to their molecular genetic characteristics. We are learning more about mechanisms of health and disease from the study of genes that are protective and deleterious. New categories of diseases have emerged, revealing that some diseases once thought to be a single entity are actually multiple distinct diseases that share similar or identical phenotypes. For instance, there are different mendelian or complex subtypes of breast cancer, Alzheimer disease, and Parkinson disease. These genetically distinct subtypes of the diseases may necessitate different treatments and have different prognoses.
The Diagnostic Utility of Family History Data
Taking a family history in pedigree form and learning how to interpret it is the single most useful action PAs can take to use the diagnostic power of genetics. The aim of collecting and analyzing family pedigree data is to identify individuals who are at risk for developing or having a multifactorial or mendelian disease. Such identification allows for screening or monitoring and possibly genetic testing, as well as patient education about lifestyle and medical prevention and surveillance practices, with the goal of reducing disease morbidity and mortality. Specifically, family pedigrees allow for the identification of patterns of inheritance, including identifying individuals at increased risk for developing different disorders. When a comprehensive family pedigree is collected, about 30% to 40% will show a significant medical disorder such as coronary heart disease (CHD) or cancer. For this and other reasons, the American Heart Association, for example, recommends regular patient questioning about family history of CHD and stroke. With the growing recognition of the value of family history data, several organizations now recommend that health care providers collect and analyze these data routinely. It is clear from several studies of clinician behavior that the use of family history data is widely underused because of several barriers inherent in our current system, with time, billing, and limitations of the electronic health record seen as the most recognized. Use of a web-based risk appraisal tool for assessing family history and lifestyle factors in primary care is being explored in those clinical settings. The U.S. Surgeon General has led a national educational effort to educate the public about the increasing importance of knowing one’s family health history and provides a free web-based, patient-completed questionnaire titled “My Family Health Portrait,” which considers six medical disorders—diabetes, colon cancer, breast and ovarian cancer, coronary artery disease, and stroke. The website ( https://familyhistory.hhs.gov/FHH/html/index.html ) provides patients with a pedigree constructed from the information input, which can be shared with other family members as well as their health care providers. Other methods used by providers to gather family history data include the use of templates in electronic medical records and structured written or electronic questionnaires given to patients. Unfortunately, these methods still require input of data and possible pedigree construction and interpretation, which take time and expertise from health care personnel.
Collecting Family History Data and Creating a Pedigree
Among the ways to collect a family history, the most efficient is a pedigree. This graphic representation of the family history can be a time-saving, inexpensive diagnostic and screening tool. When a clinician is used to taking a pedigree, it usually requires less time than writing out text, is easier to review later, and is often more concise and specific. The pedigree allows patterns of disease, if they exist, to be identified more readily. It is a record that can be easily updated or built on over several visits. Pedigrees have internationally standardized symbols that have been in use since 1995. Fig. 15.2 displays an example of a pedigree with common pedigree symbols and nomenclature.
A comprehensive family history includes at least three generations. One usually begins the family history with the patient’s health history and then extends to questions about siblings, parents, and children. If the patient is young, grandparents should be included. Questions about relatives should include information found in Tables 15.1 and 15.2 . Pertinent health information should be listed for each biological relative. This includes (1) diagnosis, (2) age at onset (AAO) or age at diagnosis (AADx) of the health condition, and (3) age and cause of death. The provider should record all the information the patient provides even if it does not seem relevant or may be incomplete at the time. Clarifications and updates can and should be made at a later time.
| Name |
| Age or year of birth (date of birth is preferable, if known) |
| Age at death and cause of death |
| Ethnic background of each grandparent |
| Relevant health information (see Table 15.2 ) |
| Relevant symptoms or diagnoses and age at diagnosis (if known) |
| Information regarding pregnancies, including infertility, spontaneous abortions, stillbirths, and pregnancy complications |
| Developmental delay and learning disabilities |
| Dysmorphic features or congenital anomalies |
| Consanguinity issues |
| Date and write your name legibly on the pedigree together with an explanation of any abbreviations |
| Alcohol abuse | Drug abuse |
| Allergies | Emphysema |
| Alzheimer disease or dementia | Epilepsy or seizures |
| Anemia | Glaucoma |
| Asthma | Hearing loss |
| Arthritis | Heart trouble |
| Birth defects or malformations | Hemochromatosis or “iron overload” |
| Any cancer | High blood pressure |
| Breast cancer | Infertility |
| Ovarian cancer | Kidney trouble (renal disease) |
| Uterine cancer | Memory loss or Alzheimer disease |
| Lung cancer | Mental illness |
| Colon or rectal cancer | Mental retardation |
| Prostate cancer | Multiple miscarriages |
| Thyroid cancer | Neurofibromatosis |
| Brain cancer | Obesity |
| Melanoma | Osteoporosis or “hip fracture” |
| Other cancer | Phenylketonuria or “metabolic” disease at birth |
| High cholesterol | Sickle cell anemia |
| Chronic infections | Smoking |
| Clotting or bleeding problems | Stillborn or infant death |
| Depression | Stroke |
| Diabetes mellitus | Violence or domestic abuse |
| Down syndrome | Other: ________________ |
Pedigree Analysis
Family pedigree data should be evaluated for the following: (1) the presence of significant medical conditions and (2) multiple family members with similar or the same disease. When two or more family members have the same or similar disease, consider the followings questions.
- •
How closely related are the family members—are they first-degree, second-degree, or third-degree relatives? (See Table 15.3 .)
TABLE 15.3
Degree of Genetic Relatedness for Different Relatives
(Wolpert CM, & Speer MC. (2005). Harnessing the power of the pedigree. Journal of Midwifery & Women’s Health, 50, 189-196.)
Degree of Relatedness
Definition and Relatives
First-degree relative
- •
Parent, full sibling, or children (offspring)
- •
A biological relative with whom the patient shares about 50% of his or her DNA
Second-degree relative
- •
Uncle, aunt, nephew, niece, grandparent, grandchild, or half sibling
- •
A biological relative with whom the patient shares about one quarter of his or her DNA
Third-degree relative
- •
First cousin, great grandparent, or great grandchild
- •
A biological relative with whom the patient shares about one eighth of his or her DNA
- •
- •
Is there a clear pattern of inheritance (e.g., mendelian inheritance), or are the family history data suggestive of a multifactorial disorder (degree of relatedness of the family members factors in here as well)?
- •
Is there an earlier AAO than expected for the condition?
- •
Is there a constellation of related conditions or diseases in relatives (e.g., depression, substance abuse, suicide)?
Table 15.4 refers to genetic “red flags” that aid the clinician in detecting whether an individual may be at-risk for a mendelian or multifactorial disease. When a pedigree shows one or more of these types of findings, the patient’s family history can be considered to be a positive family history. The findings may immediately inform clinical decision making or necessitate further investigation or referral. For instance, for a patient with a family history of two or more family members with breast cancer, screening tests such as mammography, magnetic resonance imaging, or ultrasonography can be pursued immediately. Another patient may have a pedigree showing two or more family members with an uncommon neurodegenerative disease. More information about this disease should be sought to determine what, if any, clinical decisions need to be made with the patient. It is important for the PA to review what is known about the genetics for the disorder or disease. For many diseases, the genetic information may be found in the pathology section of disease reviews; however, a number of reliable resources can help clinicians prepare themselves and their patient for the genetic referral, possible testing, anticipatory management, and longitudinal care ( Table 15.5 ).
| Red Flag | Clinical Examples |
|---|---|
| Family history of known or suspected genetic condition | Neurofibromatosis (NF1) Huntington disease |
| Multiple affected family members with same or related disorders | Diabetes mellitus type 2 in a father and son Cardiovascular disease in first-degree relatives |
| Earlier age at onset of disease than expected | Cancers: breast, ovarian, colorectal in 30s Cardiovascular disease: MI in 40s, cerebrovascular accident in 50s |
| Developmental delays or mental retardation | Fragile X syndrome Rett syndrome |
| Diagnosis in less-often-affected sex | Breast cancer in men (e.g., BRCA2 ) Cardiovascular disease (e.g., early-onset MI in women) |
| Multifocal or bilateral occurrence in paired organs | Breast or ovarian cancer Familial autosomal dominant polycystic kidney disease |
| One or more major malformations | Trisomy 13 or 21 |
| Disease in the absence of risk factors or after preventive measures | Long QT syndrome Familial hypercholesterolemia |
| Abnormalities in growth (growth retardation, asymmetric growth, excessive growth) | Turner syndrome Sotos syndrome |
| Recurrent pregnancy losses (2+) | Inherited thrombophilias Chromosomal abnormalities |
| Consanguinity (blood relationship of parents) | Hemophilia A Cystic fibrosis |
| Ethnic predisposition to certain genetic disorders | Tay-Sachs disease Thalassemias |
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