USMLE Step 1 Web Prep — Single-Gene Disorders: Part 1
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Complications that Affect Inheritance of Single Gene Diseases
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Variable expression
Incomplete penetrance
Delayed age of onset
Pleiotropy
Locus heterogeneity
New mutation
Anticipation
Imprinting
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Variable Expression
 Variation in severity of symptoms
 Some severely affected
 Others mildly affected
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Neurofibromatosis Type I
(Variable expression)
Courtesy Jorde et al: Medical Genetics, 2/ed, 2000
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Incomplete Penetrance
 Some individuals who have the disease genotype do not display disease
phenotype
 “Degree of penetrance” is the proportion of obligate carriers who display the
disease phenotype
 These are diseases in which a secondary event is required to cause expression
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Diseases Exhibiting Incomplete Penetrance
 Retinoblastoma: one copy of mutant tumor suppressor gene inherited, second copy
must be knocked out during individual’s lifetime
 Familial breast cancer: BRCA1 or BRCA2 inherited, second hit required
 Hereditary Hemochromatosis: autosomal recessive, 1 in 300 whites. Excessive iron
stores.
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Delayed Age of Onset
 Individuals with disease-causing mutation do not manifest the phenotype until later
in life
 Complicates pedigree analysis
 Examples: Huntington disease, familial breast cancer, familial colon cancer, adult
polycystic kidney disease, hemochromatosis
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Huntington Disease
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Autosomal dominant
1 in 20,000
Progressive dementia, loss of motor control, affective disorder
Trinucleotide repeat expansion disorder
Buildup of toxic protein in neurons results in neuronal death
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Pleiotropy
 A single disease-causing mutation affects multiple organ systems
 Common amongst genetic diseases
 Examples include Marfan syndrome, cystic fibrosis
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Marfan Syndrome
 Autosomal dominant
 1 in 10,000
 Mutation in fibrillin gene
 Thin, elongated limbs, hypermobile joints, frequent myopia, mitral valve prolapse
and aortic aneurysm
Courtesy Jorde et al: Medical Genetics, 2/ed, 2000
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Locus Heterogeneity
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The same disease phenotype can be caused by mutations at different loci
Often involves mutations in coding of multi-chain molecules
Example: osteogenesis imperfecta
(brittle bone disease)
mutations in collagen genes
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New Mutation
 If mortality rate for disease is high, or fertility rate low, many cases are new
mutations
 Recurrence risk for other offspring of the parents is very low
 Recurrence risk for future offspring of diseased individual follow normal patterns
 Examples: 80% of achondroplasia and 50% of neurofibromatosis type 1 cases are
new mutations
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Anticipation
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Anticipation
 Most recent generations develop disease at earlier age or greater severity
 Gradual expansion of trinucleotide repeat polymorphisms within or near a coding
gene
 Individual with few repeats is mildly or non-affected
 Increased numbers of repeats transmitted over generations causes increasing
severity or earlier onset
 Disease examples: myotonic dystrophy, Fragile X syndrome, Huntington disease
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Imprinting
 Some human genes are transcriptionally active only when transmitted by one of the
two sexes
 When a deletion occurs in a chromosome with the single active copy, the individual
has no active copies of the gene, and disease occurs
 Transcriptional inactivation is associated with methylation
 Examples are Prader-Willi syndrome and Angelman syndrome
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Prader-Willi Syndrome
 4 megabase deletion on chromosome 15q
 Transmitted by father
 Moderate mental retardation, hypogonadism, small
hands and feet, obesity
Courtesy Jorde et al: Medical Genetics, 2/ed, 2000
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Angelman Syndrome
 4 megabase deletion on chromosome 15q
 Transmitted by mother
 Severe mental retardation, seizures, ataxic gait, behavior
disorders
Courtesy Jorde et al: Medical Genetics, 2/ed, 2000
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