Blood groups, where neither of 2 alleles is dominant, are an example of what genetic characteristic?
Codominance: multiple alleles are expressed simultaneously to produce the phenotype
2 patients with neurofibromatosis I present with varying levels of severity, this is an example of what genetic characteristic?
Variable expression: the same allele is being transcribed in different ways to result in variation between individuals
If not all individuals with a mutation show the phenotype, it is considered what genetic term?
Incomplete penetrance: the allele may or may not cause disease
PKU and OI are examples of diseases where one gene impacts many, seemingly disjointed phenotypes, what is this an example of?
What is imprinting? What are the two main examples?
mutation is dependent on if the inheritence is maternal or paternal (inactivation via methylation): Prader-willi and Angelman's syndromes are examples
Addition of more trinucelotide repeats as a disease is passed down a family is an example of what?
Anticipation (like Huntington's disease): disease increases in severity as the generations increase
A patient is born with a defect in one copy of their RB gene, shortly thereafter, the second copy is mutated and the patient develops retinoblastoma. This is an example of what genetic term?
Loss of heterozygosity, we needed that last copy healthy to suppress retinoblastoma. this is only possible with tumor suppressor genes.
An increase frequency of genes that promote survival or life are a characteristic of what genetic term?
A mutated gene preventing the function of a normal gene is an example of what genetic term?
Dominant negative mutation. e.g. mutation of transcription factor in its allosteric site. A nonfunctioning mutant can still bind DNA and prevent the WT from binding
What is linkage disequilibrium?
two or more alleles are clumped together, so they tend to be inherited together more often
2 zygotes that fuse create what?
What is the term used to describe random X activation in females?
What is mosaicism?
Postfertilization loss of genetic information during mitosis
Marfan's syndrome, MEN 2B, and homocystinuria all cause a marfanoid habitus. This is an example of what?
locus heterogeneity, were mutations at many different places can cause the same phenotype
What is heteroplasmy?
presence of both normal and mutated mtDNA results in a variable expression in mitochondrial inherited disease
Offspring that receive 2 copies of chromosomes from one parent and none from the other are termed...
What is the equation for Hardy-Weinberg?
p^2 = frequency of homozygosity for p
q^2 = frequency of homozygosity for q
2pq = frequency of heterozygosity
What is the frequency of an X-linked recessive disease in males?
q, in females, q^2
What are the four assumptions of HW?
no mutation occurring at the locus, no selection, completely random mating and no migration
Patient with mental retardation, hyperpagia, obesity, hypogonadism, hypotonia. What chromosome is mutated and what is the parental origin?
Prader-Wlli syndrome: Chromosome 15, paternal origin (maternal was inactivated)
Mental retardation, seizures, ataxis, inappropriate laughter. What chromosome is mutated and what is the parental origin?
AngelMan's syndrome: chromosome 15, maternal origin (paternal is inactivated)
Genetic tree with disease in every generation and both males and females affected?
Autosomal dominant, usually present after puberty
Genetic tree with sparse disease. Skips generation. 25% of offspring from 2 carrier parents are affected.
Autosomal recessive, usually more severe and shows up early. Males and females equally affected
Genetic tree with only boys affected (squares)?
X-linked recessive. Females must be homozygous to be affected, more severe in males. incidence = gene frequency in males. No male to male transmission (50% of getting it from a carrier mother)
All females affected, but both can be affected.
X-linked dominant. Disease = penetrance in females.
Hypophosphatemic rickets or vitamin D resistant rickets is an example of what mode of inheritance?
X-linked dominant. (increased phosphate wasting in the proximal tubule that presents like rickets)
Woman to Woman transmission (affected males can't pass it on)?
Mitochondrial inheritance: mitochondrial myopathies like leber's hereditary optic neuropathy, variable expression in population due to heteroplasmy
Patient with optic neuropathy (acute loss of central vision), myoclonic epilepsy, and mitochondrial enecphalopathy are all characterized by what on microscopy?
Red ragged fibers: these are your mitochondrial myopathies
Dwarf with normal head and trunk size. What is the mode of inheritance?
Achondroplasia, AD, cell-signaling defect of fibroblast growth factor receptor 3 (associated with advanced paternal age)
45 yo male with flank pain, hematuria, hypertension, and progressive renal failure. Workup shows bilateral renal cysts. What is the mode of inheritance?
AD, this is autosomal-dominant polycystic kidney disease. 90% of cases are due to a mutation in PKD1 on chromosome 16. Complications include polycystic liver disease, berry aneurysms, mitral valve prolapse
Thousands of polyps in the colon! What is the mode of inheritance?
AD mutation of the APC gene
Tendon xanthomas and an MI before age 20. What is the mode of inheritance?
AD mutation causing elevated LDL due to defective or absent LDL receptors. This is Familial hypercholesterolemia (hyperlipidemia type IIA)
Telangiectasia, recurrent epistaxis, skin discolorations, AVMs. What is the mode of inheritance?
AD inherited disorder of blood vessels aka Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu)
Spheroid erthryocytes on peripheral blood smear and hemolytic anemia with and increased MCHC. What is the mode of inheritance?
AD hereditary spherocytosis from defect in spectrin or ankyrin defect
Depression, progressive dementia, choreiform movements, caudate atrophy and decreased levels of GABA and ACh in the brain. What is the mode of inheritance?
AD Huntington's disease from CAG trinucleotide repeat on chromosome 4. Doesn't present until 20-40
Cafe-au-lait spots, neural tumors, lisch nodules (pigmented iris hamartomas), scoliosis and optic pathway gliomas. What is the mode of inheritance?
AD mutation on chromosome 17, NF-1, Von Recklinghausen's disease or Neurofibromatosis-1
Bilateral acoustic schwannomas, juvenile cataracts. What is the mode of inheritance?
AD mutation on chromosome 22, NF-2 or neurofibromatosis-2
All MEN syndromes have what mode of inheritance?
Adenoma sebaceum, areas of hypopigmentation, cortical and retinal hamartomas, seizures, mental retardation, renal cysts, and renal angiomyolipomas, cardiac rhabdomyomas, astrocytomas. What is the mode of inheritance?
AD tuberous sclerosis. incomplete penetrance with a variable presentation
Hemangioblastoma of retina/cerebellum/medulla, bilateral renal cell carcinomas. What is the mode of inheritance?
AD von Hippel-Lindau. deletion of VHL on 3p that results in the constitutive expression of HIF (transcription factor) and activation of angiogenic growth factors
Skeletal muscle weakness, myotonia, cardiac conduction abormalities, cataracts, testicular failure, hypogammglobuliema and insulin resistance. What is the mode of inheritance?
AD. Myotonic dystrophy. CTG repeat expansion on chromosome 19
Red eyes and white hair. What is the mode of inheritance?
AR- albinism, the tyrosinase kind
What two congenital deficiencies can lead to albinism?
Tyrosinase or Defective tyrosine transporters. Result in a lack of melanin which increases the risk of cancer
What are the major autosomal recessive diseases?
Albinism, ARPKD, cystic fibrosis, glycogen storage diseases, hemochromatosis, mucopolysaccharidoses (except Hunter's), phenylketonuria, sickle cell anemias, sphingolipidoses (except Fabry's), thalassemias
Patient with recurrent S. aureus and Pseudomonas pulmonary infections, chronic bronchitis, brochiectasis, pancreatic insufficiency (malabsorption and steatorrhea), nasal polyps, meconium ileus. What is the mode of inheritance?
AR - Cystic Fibrosis defect in CFTR on chromosome 7, commonly Phe 508
A newborn suffers from a mutation causing abnormal protein folding and degradation of the CFTR channel before it reaches the cell surface. How do you treat?
N-acetylcysteine which loosens mucous pluds by cleaving the disulfide bonds in mucous glycoproteins. This is cystic fibrosis.
What is the normal function of the CFTR channel?
Active (requiring ATP) secretion of Cl- in the lungs and GI tract and actively reabsorbs it from sweat
What are the major X-linked recessive disorders?
Be Wise, Fool's GOLD Heeds Silly Hope: Burton's agammaglobulemia, Wiscott-Aldrich Syndrome, Fabry's disease, G6PD deficiency, Ocular albinism, Lesch-Nyhan, Duchenne's (and becker's muscular dystrophy), Hunter's syndrome, Hemophilia A and B
Weakness in pelvic girdle muscles progressing superiorly with pseudohypertrophy of the calf muscles and Gower's maneuver before age 5. What is the mode of inheritance?
X-R- Duchenne's muscular dystrophy, frame-shift mutation - deletion of dystrophin gene, accelerated muscle breakdown because dystrophin helps anchor the muscle fibers, particularly in skeletal and cardiac muscle
What is the type of mutation in Becker's muscular dystrophy?
Still X-R mutation of dystrophin, but less severe because it's just mutated, not a frame-shift. onset in adolescene or early childhood
Teenager with muscle weakness and atrophy. What's the next step in dx?
look for increased CPK and do a muscle biopsy. This is becker's (later onset and milder symptoms)
Contractions of the elbow, neck, weakness progressing to shoulders and hip. Cardiac conduction issues and arrhythmias by adulthood. What is the mode of inheritance?
Emery-Dreifuss muscular dystrophy: Can be either X-linked (mutation in muscular dystrophy lamin) or AD (mutation in Emerin) which can present with ONLY cardiac problems
Mental retardation, macro-orchidism, long face with large jaw, large-everted ears, autism, mitral valve prolapse, and aortic root dilation. What is the mode of inheritance?
X-R: Fragile X. defect affecting the methylation and expression of the FMR1 gene. CGG repeat
What is the trinucleotide repeat associated with Friedrich's ataxia?
What is the trinucleotide repeat associated with Huntington's disease?
What is the trinucleotide repeat associated with Fragile X?
What is the trinucleotide repeat associated with Myotonic dystrophy?
Patient with mental retardation, flat facies, prominent epicanthal folds, simian crease, duodenal atresia, and septum primum-type ASD. What is the most common event leading to this condition?
meiotic non-disjunction. Down (trisomy 21).
Brushfield spots on iris and an endocardial cushion defect with flat facies. What conditions is this patient at risk for?
Increased risk of ALL and Alzheimer's disease. (Down)
Decreased alpha-fetoprotein, increased beta-hcg, decreased estriol, increased inhibin A, and increased nuchal translucency. Karyotype shows 2 chromosome 21s. Explain the karyotype.
Down. This is a robersonian translocation which accounts for 4% of Down patients. The spare 21 is elsewhere on the karyotype.
Decreased alpha-fetoprotein, decreased b-HCG, decreased estriol, normal inhibin A. Parent wants to know prognosis.
Death within a year. This is Edwards (trisomy 18)
Severe mental retardation, rocker-bottom feet, micrognathia (small jaw), low-set ears, clenched hands, prominent occuput, congenital heart disease. What is the defect?
Severe mental retardation, rockerbottom feet, microphthalmia, microcephaly, cleft lip/palate, holoprosencephaly, polydactyly, congenital heart disease, colobomas of iris, dermal sinuses. What is seen on the fetal quad scan?
NORMAL, this is Patau's or trisomy 13. Has normal a-fetoprotein, b-hcg,estriol, inhibin A.
Microcephaly, moderate to severe mental retardation, high-pitched crying/mewing, epicanthal folds. What cardiac abnormality is most common?
This is cri-du-chat, a microdeletion of the short arm of chromosome 5 (46, XX or XY, 5p-). The most common cardiac abnormality is a VSD
Elfin faces, mental retardation, hypercalcemia, well-developed verbal skills, extreme friendliness with strangers. What is the defect?
Congenital microdeletion of chromosome 7 (including elastin gene) this is William's syndrome
Microdeletion of chromosome 22q11 can result in variable presentations. Which is characterized by thymic, parathyroid, and cardiac defects?
Microdeletion of chromosome 22q11 can result in variable presentations. Which is characterized by palate, facial, and cardiac defects?
Aberrant development of 3rd and 4th branchial pouches results in what constellation of symptoms?
CATCH-22: microdeletion of 22q11 results in cleft palate, abnormal facies, thymic aplasia, cardiac defects, hypocalcemia