Genetic Alterations Flashcards
X-linked dominant
- Described a dominant trait or disorder caused by a mutation in a gene on the X chromosome
- Both males and females express the phenotype, although, although males affected tend to have a more severe phenotype
- Only one affected X chromosome is required to cause the disease
Examples of X-linked dominant disease
- Fragile X syndrome
What is the probability pf transmitting an X-linked dominant gene mutation through the mother (female)?
- 50% probability for each child regardless of gender
- 50% affected and 50% unaffected
What is the probability pf transmitting an X-linked dominant gene mutation through the father (male)?
- 50% are affected (ALL FEMALES)
- 50% are unaffected (ALL MALES)
X-linked dominant gene mutation from an affected male to his offspring VS
X-linked dominant gene mutation from an affected female to her offspring
- Affected male to his offspring: All of his daughters and none of his sons will inherit the mutation
- Affected female to her offspring: Each child, regardless of gender, has a 50% chance of inheriting this mutation
X-linked recessive
- A mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males who are hemizygous for the gene mutation (i.e., they only have one X chromosome) and in females who are homozygous for the gene mutation (i.e., they have a copy of the gene mutation on each of their two X chromosomes)
- Males only require one mutated X chromosome (since they only have one X chromosome, to begin with) in order to cause the disease
- Phenotype expressed in males only
- Affected males are always related to each other through females. MALE –> TO MALE TRANSMISSION DOES NOT OCCUR
- Females are less likely to have an x-linked recessive disorder because they have two X chromosomes
- If females do inherit it, it will most likely be less severe
Examples of X-linked recessive disorders
- Hemophilia
- Fabry disease
Autosomal Dominant
- Describes a trait/disorder in which the phenotype is expressed in those who have inherited only one copy of a particular gene mutation (heterozygotes)
- Specifically refers to a gene on one of the 22 pairs of autosomes (non-sex chromosomes)
- Only one copy of the abnormal gene
- Not sex linked
What is the chance of passing on an autosomal dominant disorder from parent to offspring?
- Each offspring has a 50% chance of inheriting it
- Son and daughters of an affected parent are equally likely to inherit and transmit the disorder
Examples of autosomal dominant disorders
- Huntington disease
- Marfan syndrome
Autosomal Recessive
- Describes a trait/disorder requiring the presence of two copies of a gene mutation at a particular locus in order to express the observable phenotype
- Refers to genes on one of the 22 pairs of autosomes (non-sex chromosomes)
-
Needs two copies of the mutation for an offspring to exhibit the phenotype
- Generally seen in a single generation of a family
- Each offspring has a 25% chance of inheriting it
Examples of autosomal recessive disorders
- Cystic fibrosis
- Sickle cell disease
What is the probability of transmitting an autosomal recessive gene mutation to an offspring if one parent carries the mutation?
- 50% are carriers
- 50% are non-carriers
- NO ONE SHOWS!
What is the probability of transmitting an autosomal recessive gene mutation to an offspring if both parents carry the mutation?
- 25% are noncarriers and 50% are carriers } (unaffected)
- 25% are homozygotes for the mutation (affected)
What is the probability of transmitting an autosomal recessive gene mutation to an offspring if one parent is affected and one parent is a carrier of the mutation?
- 50% are carriers (unaffected)
- 50% are homozygotes for the mutation (affected)
Identify 7 disorders/diseases with a strong familial history
- CAD
- Stroke
- HTN
- Cancer
- Diabetes
- Pulmonary conditions
- Mental Illness
What increases an individual’s genetic susceptibility to developing CAD?
- Two or more closed relatives with CAD
- Female relatives with CAD
- Presence of related disorders such as diabetes in a close relative
- Presence of multiple established/emerging risk factors in close family members
- Early-onset of CAD ( <55 for men, <65 for women)
What two common genetic variants or single-nucleotide polymorphisms (SNPs) were consistently associated with total stroke (all types) and ischemic stroke in white individuals?
- Located on chromosome 12p13 near the gene NINj2, which encode ninjurin 2
What is GINA and how is it related to genetic discrimination?
- Stands for Genetic Information Non-Discrimination Act
- A federal law passed in 2008
- Prohibits discrimination in employment and health insurance coverage based on genetics
- Prohibits insurance companies from requesting/requiring genetic information of an individual or their family, or using genetic information for decisions regarding coverage, rates, or preexisting conditions
What is one thing GINA does not do?
- It does not extend to:
- Life insurance
- Disability insurance
- Long0term care insurance
What does a patient need to be aware of before they order a genetic test?
- Patients need to be aware that they need to have purchased forms of insurance (life, disability, long-term care) prior to genetic testing
Mutations in BRCA 1 and BRCA 2 genes are associated with what?
- Hereditary breast and ovarian cancer
When BRCA 1 and BRCA 2 genes are functioning normally, what do they act as?
- They both act as tumor suppressor genes
On what chromosomes do BRCA 1 and BRCA 2 mutations occur?
- BRCA 1 occurs on chromosome 17
- BRCA 2 occurs on chromosome 13
How are the mutations for HFE inherited?
- They are inherited in an autosomal recessive manner
What is HFE associated hereditary hemochromatosis (HFE-HH) and what are the signs and symptoms?
- A condition in which there is high absorption of iron from the intestinal mucosa
-
Signs/Symptoms:
- Excessive storage of iron in the liver, skin, pancreas, heart, joints, and testes
- Abdominal pain
- Weakness
- Lethargy
- Weight loss
What are the two most common mutations associated with HFE-HH and on which chromosome are they located?
- p. Cys282T yr and p.His63Asp yr
- An individual can be homozygous for the p. Cys282 T yr mutation (greater risk for iron overload)OR
- A compound heterozygote for both mutations ( p. Cys282T yr and p.His63Asp yr)
- They are located on chromosome 6
At what age do symptoms usually occur for HFE-HH?
- Between the ages of 40 to 60 years
What is a major complication of HFE and what can worsen it?
- Liver cirrhosis –> Individuals treated prior to the onset of cirrhosis have a normal life span
- Alcohol consumption can worsen symptoms
What is the recommended treatment for HFE-HH?
- Weekly periodic phlebotomy until serum ferritin levels are 50ng/ml or lower
Is there genetic testing available for “normal” ( age of onset >60 years and not associated with an extensive family hx of AD) AD?
- There is no current genetic testing available for “normal” AD
- The association of the APOE e4 allele with AD is insignificant
What is familial AD (FAD)?
- FAD characterizes families that have more than one member with AD and usually implies multiple affected persons in more than one generation
What does early-onset FAD (EOFAD) refer to?
- EOFAD refers to families in which the onset is consistently before the age of 60 to 65 years and often before the age of 55 years
What percentage of early-onset AD is familial and what percentage is inherited in an autosomal dominant manner?
- Approximately 60% of early-onset AD is familial
- Approximately 13% is inherited in an autosomal dominant manner
What are the three types of early-onset AD?
- AD1
- AD3
- AD4
AD1 is caused by mutations on what gene located on what chromosome?
- Caused by mutations in APP located on chromosome 21
AD3 is caused by mutations on what gene located on what chromosome?
- Caused by mutations in PSEN1 gene located on chromosome 14
AD4 is caused by mutations on what gene located on what chromosome?
- Caused by mutations in PSEN2 located on chromosome 1
What type of genetic testing is available for the three types of early-onset AD?
- Molecular genetic testing is available for the three types of early-onset AD (AD1, AD3, AD4)
- There is NO treatment however
What is genomics?
- The study not just of single genes but of the functions and interactions of many genes in the genome.
How does the study of genomics affect healthcare?
- Understanding how variations in an individual’s DNA may affect disease and health is the focus of genomic medicine. This knowledge can lead to:
- Innovative ways to diagnose disease
- Earlier detection, by identifying genetic predisposition to a particular disease
- New approaches to treatment
- Development of designer drugs that target a mutation or its products (pharmacogenomics)
What is penetrance?
- The proportion of individuals with a mutation causing a particular disorder who exhibit clinical symptoms of that disorder
- Most often refers to autosomal dominant conditions
- A greater penetrance means that it is more likely an offspring will have it
How do you calculate penetrance?
Number of individuals with clinical features (Nclinical)
——————————————————————————X 100 = Penetrance
Number of individuals with a disease-causing mutation (Nmutation)
What does complete penetrance refer to?
- Refers to clinical symptoms being present in all individuals who have the disease-causing mutation
What does incomplete penetrance refer to?
- Refers to clinical symptoms not being present in all individuals who have the disease-causing mutation
What does consanguinity refer to?
- Refers to genetic relatedness between individuals descended from at least one common ancestor –> Incest
- Can decrease genetic variability
- Increases risk for mutations
What does anticipation refer to?
- Refers to the tendency in certain genetic disorders for individuals in successive generations to present at an earlier age and/or with more severe manifestations
Anticipation is often observed in disorders resulting from what?
- Often is observed in disorders resulting from the expression of a trinucleotide repeat mutation that tends to increase in size and have a more significant effect when passed from one generation to the next
- Example: Huntington Disease
Genotype VS phenotype?
- Genotype: Refers to the genetic makeup/composition
- Phenotype: The observable physical/biochemical characteristics of the expression of a gene; the clinical presentation of an individual with a particular genotype
What are predictive and pre-symptomatic genetic tests?
- Used to find gene changes that increase a person’s likelihood of developing diseases in asymptomatic individuals with a family history of a genetic disorder and a potential risk of eventually developing the disorder
What are the two types of predictive testing?
- Presymptomatic testing
- Predispositional testing
What is presymptomatic testing?
- Refers to testing of an asymptomatic individual in whom the discovery of a gene mutation indicates certain development of findings related to a specific diagnosis at some future point
- A negative result excludes the diagnosis –> Means NO mutation was found
- Mutation found –> Means individual will develop disorder at a future point
What is predispositional testing?
- Refers to testing an asymptomatic individual in whom the discovery of a gene mutation indicates the eventual development of findings related to a specific diagnosis is likely, but not certain
- Mutation confers susceptibility
- Mutation found –> Higher risk of developing disorder but not 100%
- Mutation NOT found –> Lower risk of developing disorder but not 0%
What does carrier testing used for?
- Used to find people who “carry” a change in a gene that is linked to a disease
- Usually offered to people who have a family history of a specific inherited disease or who belong to certain ethnic groups that have a higher risk of specific inherited diseases
What type of gene mutations is carrier testing used for?
- Used for autosomal recessive gene mutations
What is pharmacogenomic testing used for?
- Provides information about how certain medications are processed by an individual’s body
- Helps providers choose medicines that work best for an individual’s genetic makeup
What is diagnostic testing?
- Testing used to confirm or exclude a known or suspected genetic disorder in a symptomatic individual or, prenatally, in a fetus at risk for a certain genetic condition
Define epigenetics
- Processes that modulate how a given set of genomic information gives rise to a phenotype
- Refers to the area outside of the gene area
- Environment has an impact on this
