Introduction+to+Molecular+Medicine+and+Medical+Genetics

=**Objectives**=


 * 1. Acquire an appreciation for the fact that virtually all disease have a genetic component** (p.336)

All disease have a genetic component. Either genetics directly causes a disease or provides susceptibility for the disease.


 * 2. Differentiate among the four types of genetic disease** (p.338)

__Single Gene (Mendelian)__ Numerous, but individually rare. Clear pattern of inheritance in most cases and high risk for relatives with the highest risk for first degree relativees.

__Multifactorial__ Common disorders. No clear pattern of inheritance with low or moderate risk for relatives.

__Chromosomal__ Not always a clear pattern of inheritance. Risk to relatives dependent on type of abnormality and is a common cause of pregnancy loss.

__Somatic Mutation__ Aquired mutations resulting in neoplasia


 * 3. Acquire an appreciation for the impact of genetic disease in prenatal, perinatal, and postnatal settings.** (p.338)

Different genetic diseases tend to be detected at different times in life. Most chromosomal disease are detected prenatally with very few being undetected after birth. However, multifactorial defects tend to remain undetected until well into adulthood. Single gene (mendelian) defects are often detected perinatally, escaping detection prenatally and rarely remaining undetected until adulthood.


 * 4. Review the types and frequencies of genetic disease in the population** (p.339)


 * Type**||**Frequency by 25 years**||**Frequency after 25 years**||**Lifetime Frequency**||
 * Chromosomal Disorders||1.8 / 1,000||2 / 1,000 ||3.8 / 1,000||
 * Single Gene Disorders||3.6 / 1,000||16.4 / 1,000||20 / 1,000||
 * Multifactorial (Part-Genetic) Disorders||46.4 / 1,000||600 / 1,000||646.4 / 1,000||
 * Somatic Cell (Cumulative) Genetic Disorders||--||240 / 1,000||240 / 1,000||


 * 5. Differentiate between genetic determinism and genetic susceptibility** (p.340)

Genetic determinism refers to genetic defects that determine a disease while genetic susceptibility refers to genetic defects and confer susceptibiity to getting a disease.

That is, in genetic determinism, a woman heterozygous for an X-linked genetic disorder has a 50% risk of passing on the disease to her male children; if the male children do inherit the genetic defect, they will develop the disease. However, if the genetic disorder confers genetic susceptibility instead, then her male descendents who inherit this risk are more susceptible to getting the disease but not guarenteed to develop the disease.


 * 6. Consider both the myths and realities of the Human Genome Project** (p.343)

__Myths__ We will know the cause of all disease. Disease can be predicted and prevented. Gene therapy can be the silver bullet.

__Realities__ We will know all the genes. Presymtomatic testing works, if you have a treatment for the disease. Differential diagnosis/prognosis/management is possible. Genetic variation can be used as a discriminator.


 * 7. Describe the potential benefits of the Human Genome Project on Health Care** (p.343)

Benefits of the human genome project incldue new patients, improved diagnositic efficiency (genomic triage), intellectual property, translational research, single nucleotide polymorphism profiles for the prediction of disease susceptibility and pharmacogenetics.


 * 8. Review the basic principles of Molecular Pathology including the mechanisms of DNA mutation and possible outcomes associated with DNA damage** (p.346)

Chemical insult, DNA modification, or physical insult can result in altered genomic DNA. Chemical insult includes N-nitroso compounds, polycyclic aromatic hydrocarbons, and crosslinking agents. DNA modification can occur via transposons, unequal crossing over, or segmental genome duplication. Physical insult can include ionizing radiation and ultraviolet radiation. Damaged DNA can be corrected by DNA repair mechanisms (nucleotide excision repair, enzymatic reversal). However, deficiencies in DNA repair can result in the generation of stable DNA mutations.


 * 9. Describe the various types of DNA damage** (p.345)

__Types of Genetic Mutations__ Aneuploidy - alteration in the number of copies of genome Chromosomal abnormalities - duplicated chromosomes, breakages and incorrect reattachment Gene amplification - increase in gene copy number Gene mutation - point mutation, insertional mutation, deletions

__Molecular Collection of Gene Mutations__ Point mutations - alternation of individual nucleotides in a gene sequence. Missense mutations may or may not change the coded amino acid. Nonsense mutations produces a stop codon where an amino acid should be. Insertional mutations - additon of nucleotides that disrupt the coding sequence of a gene. Can result in a frameshift that alters the reading frame downstream of the mutation or in-frame mutation that results in the loss of amino acids within the frameshifted region but recovery of reading frame afterwards. Deletion - Loss of nucleotides Splicing mutation - errors in splicing resulting in formation of exonic splice sites or cryptic slplice sites (i.e., a splice site where there shouldn't be one) or exon skipping (loss of a splice site)


 * 10. Review the advantages and limitations of molecular genetic testing as well as present and future molecular diagnostic techniques including DNA microarray technology** (p.353)

__Advantages__
 * Unambigous determination of the presence or absence of a mutation
 * Diagnosis can be made well in advance of symptoms
 * Can distinguish between disorders of similar phenotypes
 * Identifying specific mutation may be prognostically significant
 * DNA from peripheral blood allows for more non-invasive procedures
 * Chroionic villi or amniotic fluid cells can be used for prenatal testing

__Limitations__
 * Heterogeneity of genetic changes that underly inherited disorders (allelic heterogeneity)
 * State-of-the-art diagnostics and curative therapies lag behind gene testing
 * Insurance and employment discrimination
 * Some molecular tests are costly and not covered by insurance (or patient doesn't want the insurer to know they are being tested)


 * 11. Acquire an appreciation for the importance of genomic medicine in the primary care setting.** (p.357)

Physicans armed with genomic medicine in the primary care setting will be able to move from intense, crisis-driven intervention to preventative medicine by utilizing genomic tests to identify individual susceptibility to common disorders such as heart disease, diabetes, and cancer. Identification of a genomic profile consistent with an elevated risk would lead to primary prevention (diet and exercise) and secondary prevention (early detection or pharmacologic intervention). Screening will be based on importance of a given condition to public health, availability of a highly sensitive genomic assay, availability of pre-symptomatic treatment, and cost considerations


 * 12. Describe the barriers to provision of genetic services as they exist in medicine today.** (p.358)

__Barriers__
 * Lack of genetic knowledge
 * Lack of detailed/updated family history
 * Lack of referral guidelines or tools to facilitate their use
 * Lack of confidence for delivering genetic services, assessing, and managing risk
 * High cost of services
 * Funding resources
 * Insurance problems
 * Perception of limited or no benefit from genetic services
 * Skepticism about validity/utility of genetic testing
 * No information on how to manage moderate risk for genetics-related disease