What is true of genetic diseases with variable expression?
The nature and severity of the phenotype varies from one individual to another with the same disease
What is true of genetic diseases with incomplete penetrance?
Not all individuals with the mutant genotype will show the complete mutant phenotype
What is the significance of imprinting in genetic diseases?
A genetic disease has a different phenotype depending on whether the mutation is inherited from the mother or from the father
What is meant by linkage disequilibrium?
Measured in a population, it is the tendency for certain alleles at two linked loci to occur together more often than expected by chance
What term describes the situation in which cells in the body have a different genetic makeup?
What is the name of the phenomenon whereby a genetic disease has an earlier onset or worsening severity in each subsequent generation?
What word describes the phenomenon of a single gene having more than one effect on an individual's phenotype?
Prader-Willi and Angelman syndromes are the result of which genetic process?
The random inactivation of one X chromosome in females
A patient has inherited a mutation in a tumor suppressor gene. Mutation of the remaining (previously normal) copy of the tumor suppressor gene represents a loss of _____, which may lead to the development of cancer.
Heterozygosity; the patient was previously a heterozygote for lost tumor suppressor gene and both genes must be lost for oncogenesis
True or False? Oncogenes, in a manner similar to tumor-suppressor genes, must have a deletion/mutation in the complementary allele before cancer develops.
False; the mutation of a single oncogene can produce cancer
A genetic disease that shows _____ _____ will have mutations at different loci that produce the same phenotype.
True or False: Albinism is an example of a genetic disease that demonstrates locus heterogeneity.
What is an example of a genetic disease that displays anticipation?
The presence of both normal and mutated mitochondrial DNA, resulting in variable expression in mitochondrial inherited diseases
What is the significance of a dominant negative mutation?
A nonfunctional altered protein that also prevents the normal gene product from functioning
Name a disease whose pathogenesis involves loss of heterozygosity.
The tendency for certain alleles to be inherited together more often than is expected by chance is called what?
True or False? The Hardy-Weinberg law assumes that there are no mutations at the locus being studied.
What equation describes the disease prevalence in a population that is in Hardy-Weinberg equilibrium?
p2 + 2pq + q2 = 1; where q2 is the prevalence of an autosomal recessive disease
What is the heterozygote prevalence in a population that is in Hardy-Weinberg equilibrium?
In Hardy-Weinberg population genetics, what do p and q represent?
Alleles of a gene
What are the four assumptions of the Hardy-Weinberg equation?
No mutation occurring at the locus; no selection for any of the genotypes at the locus; completely random mating; no migration
The prevalence of which type of genetic disease is indicated by q in males and q2 in females in Hardy-Weinberg genetics?
X-linked recessive diseases
How is Prader-Willi syndrome inherited?
It is inherited via the deactivation of paternal copies of genes on chromosome 15
In genetics, what does the term imprinting refer to?
When, at a single locus, one allele is inactivated by methylation (an inherited condition) and one allele is not (disease occurs as the result of the loss of the active allele)
How is Angelman syndrome inherited?
Via the deactivation of the maternal copies of genes on chromosome 15; via chromosomal deletion, faulty imprinting, or uniparental disomy
Where is the gene located in Prader-Willi syndrome? In Angelman's syndrome?
Both syndromes are due to inactivation or deletion of genes on chromosome 15
What are the signs of Prader-Willi syndrome?
Mental retardation, obesity, hypogonadism, and hypotonia
What are the signs of Angelman's syndrome?
Mental retardation, seizures, ataxia, and inappropriate laughter (happy puppet syndrome)
In Leber's hereditary optic neuropathy, vision loss is _____ (central/peripheral).
Autosomal-dominant patterns of inheritance are often found in diseases caused by defects in _____ genes.
Structural; as opposed to recessive diseases, which are often caused by faulty enzyme genes
True or False: A mother with an X-linked dominant disease may pass the disease only to her sons.
False; both her sons and her daughters may be affected
True or False? Patients with autosomal-dominant disorders often present clinically after puberty.
True; in order for the diseases to remain in the population, affected people must have offspring
What is the pattern of inheritance of hypophosphatemic rickets?
What is the mode of inheritance if a disease is present in many generations and affects both males and females in roughly equal proportions?
What is the mode of inheritance in a family in which a disease is transmitted only through the mother and all children (both boys and girls) are affected?
Autosomal-recessive patterns of inheritance are often found in diseases caused by defects in _____.
Enzymes; as opposed to dominant diseases, which are often caused by faulty structural genes
True or False? A mother may pass a disease with a mitochondrial pattern of inheritance to both her sons and her daughters.
What is the mode of inheritance if a gene is present in a single generation and 25% of the offspring from the same two parents have the disease?
What is the pattern of inheritance of Leber's hereditary optic neuropathy?
Do patients with dominant or recessive diseases generally present at a younger age?
What would you expect to see on urinalysis in a patient with hypophosphatemic rickets?
You would expect an increased urine phosphate level since there is proximal tubule phosphate loss
Variable expression of mitochondrial diseases can be accounted for by what phenomenon?
True or False? Hypophosphatemic rickets can be treated by vitamin D supplementation.
False; this disease is also known as vitamin D-resistant rickets
What is the mechanism of phosphate wasting in hypophosphatemic rickets?
There is increased phosphate wasting at the proximal renal tubule
Which cells are affected in Leber's hereditary optic neuropathy?
There is degeneration of retinal ganglion cells and their axons
In general, are autosomal dominant or autosomal-recessive disorders more severe?
What is the mode of inheritance in a family in which 50% of sons are affected and there is no male-to-male transmission?
What percentage of sons of a carrier mother are expected to inherit an X-linked recessive disease?
True or False? X-linked recessive diseases are commonly more severe in males than in females.
True or False? A mother with an X-linked dominant disease may pass the disease to either her sons or her daughters.
True or False? A father with an X-linked dominant disease will pass the disease to all of his daughters but none of his sons.
A mother with achondroplasia is pregnant; assuming that the father does not have this condition, what is the likelihood that her child will also have the disease?
50%; achondroplasia is an autosomal-dominant disease
Achondroplasia is the result of a defect in the _____ receptor.
Fibroblast growth factor 3
Describe the clinical manifestations of achondroplasia.
Patient has dwarfism with short limbs but a normally sized head and trunk
What parental attributes are associated with achondroplasia?
Advanced paternal age
What is the mode of inheritance of autosomal-dominant polycystic kidney disease?
Autosomal-dominant polycystic kidney disease is associated with what cardiac pathology?
Mitral valve prolapse
A 50-year-old man has hematuria, hypertension, and progressive renal failure. His kidneys are both massively dilated as a result of multiple large cysts. What is the most likely diagnosis?
Autosomal-dominant polycystic kidney disease
What three nonrenal pathologies are associated with autosomal-dominant polycystic kidney disease?
Polycystic liver disease, berry aneurysm, and mitral valve prolapse
Ninety percent of cases of adult polycystic kidney disease are associated with a mutation in what gene?
APKD1, which is located on chromosome 16 (remember: 16 letters in polycystic kidney)
Adult polycystic kidney disease is inherited in an autosomal-_____ (dominant/recessive) pattern, whereas infantile polycystic kidney disease is associated with an autosomal-_____ (dominant/recessive) pattern.
What is the mode of inheritance of familial adenomatous polyposis?
What is the prognosis for a patient with familial adenomatous polyposis?
Adenomatous polyps will progress to colon cancer unless they are resected
The defect that leads to familial adenomatous polyposis is found on chromosome ____.
5 (remember: 5 letters in polyp)
The defect that leads to familial adenomatous polyposis is found in the ____ gene.
APC (remember, it stands for Adenomatosis Polyposis Coli)
What is the mode of inheritance of familial hypercholesterolemia?
Familial hypercholesterolemia is the result of a defect in what type of receptor?
Low-density lipoprotein receptor
In patients with familial hypercholesterolemia, heterozygotes can be expected to have a cholesterol level around ____ mg/dL, and homozygotes can be expected to have a cholesterol level around ____ mg/dL.
A middle-aged woman had a myocardial infarction 20 years ago, and has tendon xanthomas on her Achilles tendon. What is the most likely diagnosis?
What is another name for Osler-Weber-Rendu syndrome?
Hereditary hemorrhagic telangiectasia
Why is recurrent epistaxis a common finding in Osler-Weber-Rendu syndrome?
Malformed blood vessels in the nose can break and cause frequent nosebleeds
A patient has multiple telangiectasias, skin discolorations, and notes recurrent epistaxis; what other physical finding might be expected?
This constellation of symptoms is typical of hereditary hemorrhagic telangiectasia; can also see arteriovenous malformations
What is the mode of inheritance of hereditary spherocytosis?
A patient has hemolytic anemia, increased mean corpuscular hemoglobin concentration, and spheroid erythrocytes. What is the most likely diagnosis?
Why do patients with hereditary spherocytosis have elevated mean corpuscular hemoglobin concentration?
Red blood cells have less surface area and volume and therefore more concentrated hemoglobin
Describe the clinical manifestations of hereditary spherocytosis.
Symptoms associated with anemia such as fatigue, shortness of breath, pallor, and dark urine
In refractory cases, how can you cure hereditary spherocytosis?
A splenectomy is curative
What is the mode of inheritance of Huntington's disease?
A 50-year-old patient develops depression, progressive dementia, and choreiform movements. What is the most likely diagnosis?
Huntington's disease; symptoms usually begin between 20 and 50 years of age
You are performing an autopsy on a man who had Huntington's disease; what would you find on inspection of the brain?
Huntington's disease is associated with atrophy of the caudate
The defect that leads to Huntington's disease is found on chromosome ____.
4 (remember: Hunting 4 food)
What would a genetic analysis of a patient with Huntington's disease demonstrate on chromosome 4?
Trinucleotide repeats of (CAG)n in the Huntingtin gene
Which neurotransmitters are most affected by Huntington's disease?
Decreased levels of γ-aminobutyric acid and acetylcholine
What is the mode of inheritance of Marfan's syndrome?
Marfan's syndrome is the result of a mutation in the _____ gene.
What physical signs are associated with Marfan's syndrome?
Marfan's syndrome is associated with a tall habitus and long, tapering fingers and toes
True or False? Marfan's syndrome is associated with hyperflexible joints.
What pathology of the cardiovascular system is seen in Marfan's syndrome?
Cystic medial necrosis of the aorta, aortic incompetence, and dissecting aortic aneurysms
Marfan's syndrome is associated with what ocular pathology?
Subluxation of the lenses
What is the inheritance pattern of multiple endocrine neoplasias?
These syndromes are inherited in an autosomal dominant fashion
How many syndromes are considered multiple endocrine neoplasias?
Three, known as MEN I, MEN II, and MEN III
Name 5 endocrine organs that develop tumors in the multiple endocrine neoplasia syndromes.
Pancreas, pituitary, parathyroid, thyroid, and adrenal medulla
Which gene mutation causes multiple endocrine neoplasias 2A and 2B?
A tall male patient enters the emergency room with the combination of a dissecting ascending aorta and acute mitral valve prolapse; what disorder might explain these findings?
Marfan's syndrome is associated with cystic medial necrosis of the aorta which may lead to a dissection, as well as a floppy mitral valve prone to prolapse
What is the mode of inheritance of neurofibromatosis type 1?
What is another name for neurofibromatosis type 1?
von Recklinghausen;s disease
Neurofibromatosis type 1 (von Recklinghausen's disease) is associated with a mutation on which chromosome?
Chromosome 17 (remember: there are 17 letters in von Recklinghausen)
A patient has caf-au-lait spots, Lisch nodules, scoliosis, neural tumors, and pheochromocytoma. What is the most likely diagnosis?
Neurofibromatosis type 1 (von Recklinghausen's disease)
What is another term for the pigmented iris hamartomas associated with neurofibromatosis?
What are the dermatologic findings in neurofibromatosis type 1?
Caf au lait spots and axillary freckling
What neoplasms are associated with neurofibromatosis type 1?
Neural tumors, optic pathway gliomas, pheochromocytoma, and overall increased tumor susceptibility
What is the mode of inheritance for neurofibromatosis type 2?
A patient has bilateral acoustic neuroma, optic pathway gliomas, and juvenile cataracts. What is the most likely diagnosis?
Neurofibromatosis type 2
True or False? Neurofibromatosis type 2 is associated with skin findings that are similar to those of neurofibromatosis type 1.
False; neurofibromatosis type 2 is not associated with abnormal skin findings
Neurofibromatosis type 2 is a result of a mutation in the gene _____ found on chromosome _____.
NF2, 22 (remember: Type 2 = 22)
What is the mode of inheritance of tuberous sclerosis?
A patient has adenoma sebaceum on his face, ash leaf spots on his trunk, mental retardation, and seizures. What the most likely diagnosis?
What renal findings might distinguish a patient with tuberous sclerosis from a patient with adult polycystic kidney disease ?
While both will have renal cysts, tuberous sclerosis is associated with renal angiomyolipomas
What is a cardiac manifestation of tuberous sclerosis?
Compared to the general population, patients with tuberous sclerosis have an increased incidence of which brain tumor?
True or False? All patients who inherit the gene in tuberous sclerosis will display very similar signs and symptoms.
False; although autosomal dominant, this disease has incomplete penetrance and a variable presentation
What is the mode of inheritance of von Hippel-Lindau disease?
A patient has hemangioblastomas of the retina and cerebellum, as well as bilateral renal cell carcinoma. What is the most likely diagnosis?
von Hippel-Lindau disease