Genetic Principles

• Codominance
– both allelic copies are expressed
• Example - blood groups (A, B, AB)
• Variable expression
– nature and degree of phenotype vary from 1 individual to another
with the same mutation
• Example 2 patients with neurofibromatosis may have varying disease severity
• Incomplete penetrance
– not all individuals with a mutant genotype have diseased phenotype
• explanation for a dominant disease "skipping" a generation
– penetrance can be calculated by ( # with symptoms) / (# with disease
genotype)
• if parents have a 50% chance of giving defective gene but the penetrance is
50% - 0.5 x 0.5 x100 = 25% of recurrence
– Example - familial breast cancer due to mutations in the BRCA1 gene
• Pleiotropy
– single mutation has diverse effects upon several organ systems
– Example - Phenylketonuria
• Anticipation
– changes in disease presentation in succeeding generations
– ↑ severity
– earlier onset 
– caused by trinucleotide expansion 
• region of repeating triplets expands in each generation
• Example - Huntington's disease, fragile X, myotonic dystrophy, Friedreich
ataxia
• Loss of heterozygosity
– "two-hit model"
– individual inherits or develops a mutation in one copy of gene
• disease occurs when the complementary allele is lost
– e.g. tumor suppressor diseases (Li-Fraumeni, retinoblastoma)
• Dominant negative mutation
– mutant gene product antagonizes wild-type gene
product
– exerts a dominant effect
– e.g.) common in multimeric proteins where one mutant
subunit can change function of entire enzyme
• De novo mutation
– genetic disease in an individual with no familial history
– recurrence risk for offspring of same parents is low
• Locus heterogeneity 
– different mutations can produce the same phenotype
– e.g., marfanoid habitus caused by
• Marfan's syndrome, MEN 2B, homocystinuria
• Heteroplasmy 
– presence of both normal and mutated mitochondrial (mt)DNA
in the same cell
– results in variable expression in mitochondrial inherited
disease
• Uniparental disomy 
– offspring receives both copies of a chromosome from 1 parent
– no copies from the other parent
– causes disease if the chromosome is usually imprinted
– Example – Prader-willi syndrome, Angelman Disease syndrome
• Polygenic inheritance 
– multiple genes are responsible for inheritance of a disease
– Example - androgenic alopecia
• Heritability
– can measure the relative effect of genetic vs.
environmental factors on a phenotype
– calculated by phenotypic relationship between dizygotic
(DZ) and monozygotic (MZ) twins
• heritability = (CMZ-CDZ) / (1-CDZ)
– where C = concordance
– prevalence of disease in both twins
– entirely environmental disease should have CMZ = CDZ
– entirely genetic disease should have CMZ=1.0 and CDZ=0.5
» siblings share 50% of their genes
• A 3-year-old is brought to the pediatrician by his mother because she is
concerned about recent changes to his behavior. She states that he has
seemed to regress in his motor development and has been having
occasional brief episodes of uncontrollable shaking. During the
subsequent work up, a muscle biopsy is obtained which demonstrates
red ragged fibers and a presumptive diagnosis of a genetic disease
made. The mother asks if her other son will be affected. What should be
the physician's response?
• A. There is a 100% he will be affected, but the severity may be different
• B. There is a 25% chance he will be affected
• C. He will be unaffected
• D. There is a 100% he will be affected, and the severity will be the same
• E. There is a 50% chance he will be affected
• A 35-year-old male is brought to the physician by his wife who is
concerned because he has begun to demonstrate odd behavior which
has worsened over the past several months. She states that he has
become very aggressive and at times will have sudden, jerky movements
which he is unable to control. The patient states that his father had the
same problem which he died of at age 69. The patient had a recent,
"cold," with fevers, chills and, "throat pain," which resolved on its own,
"some time ago." Which of the following is true of this disease?

• A. A mutation in ATP7B on chromosome 13 is responsible

• B. Erythema marginatum is a complication associated with this disease
• C. Overactivity of dopamine in the mesolimbic pathway is the underlying
pathology
• D. Underactivity of dopamine in the nigrostriatal cortex is the underlying
pathology
• E. It demonstrates anticipation
• A mother brings her 3-year-old daughter to the pediatrician because she is
concerned about her development. She states that her daughter seemed to
regress in her motor development. Furthermore, she states she has been
having brief episodes of uncontrollable shaking, which has been very
distressing to the family. During the subsequent work-up, a muscle biopsy is
obtained which demonstrates red ragged fibers and a presumptive diagnosis
of a genetic disease is made. The mother states that she has another 6-year-
old son who does not seem to be affected or have any similar symptoms.
What genetic term explains this phenomenon?

• A. Allelic heterogeneity
• B. Phenotypic heterogeneity
• C. Genetic heterogeneity
• D. Heteroplasmy
• E. Locus heterogeneity