USMLE Genetics – Flashcards
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Recognize a mode of inheritance Predict the recurrence risk of a disease, say in an unborn child Identify an OBLIGATE carrier for disease
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What are the three things a USMLE question about genetics will ask you to do using a pedigree?
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Multiply the odds of the baby being affected IF the mother was a carrier (1/4) by the chances of her BEING a carrier (X, or say 1/10)--- 1/40
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How do you determine the probability of an unborn child being affected by an AR trait when you know the father is a carrier and the mother has probability X of being a carrier?
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X time Y multiplied by the chances of being affected IF bother are carriers, which is 1/4 so X*Y*1/4
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How do you determine the probability of an unborn child being affected by an AR trait when you only know the Father has chance X of being and carrier and the Mother has chance Y of being a carrier
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Normally X inactivation occurs in all cells of the female so one X works and the other doesn't. This is normally about 50/50 so even if half the cells dont make an enzyme, such as HGPRT, this is still enuf to get by ...IF in a rare case and due to bad luck all the good X-chromosomes get turned off...They will manifest the symptoms of HGPRT even tho they are a heterozygote
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What is a manifesting heterozygote?
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The nature and severity of a phenotype varies widely between individuals (often explained by the type of mutation to blame, missense v nonsense.) ALL people affected have symptoms
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What does Variable Expression mean?
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NF1 and Hemochromatosis...manifestation depends on how much iron you accumulate and how much you lose.
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What are two examples of disease that exhibit variable expression?
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When some individuals who have the disease GENOTYPE do not manifest the disease phenotype for some reason... Degree of penetrance is used...90% penetrant is someone with a 90% chance of getting the manifestations.
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What is Imcomplete Penetrance?
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A skipped generation in an AD disease where the mother or father and children of a generation have the disease but the person does not.
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How does incomplete penetrance manifest on a pedigree?
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BOTH genes must be mutated to get the symptoms. If you inherit one mutation, you have a 90% chance of acquiring another...Imcomplete penetrance.
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What might be a reason for incomplete penetrance in Retinoblastoma, for example?
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When a normal heterozygote for a TUMOR SUPPRESSOR GENE gets a mutation in the remaining good gene, they become symptomatic and have 'LOST their heterozygosity.'
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What is a loss of heterozygosity?
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Multiply their risk of GETTING the mutation by the penetrance, 90%.
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How do you determine the recurrence risk of an offspring developing a disease which is only 90 percent penetrant?
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The idea that 1 gene has more than 1 effect on the body (ie effect on more than 1 Part of the body...) Seen in Marfans, for example. (AD)
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What is pleitropy?
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When one disease can be caused by mutations in more than one gene...OI or Albinism for example.
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What is Locus heterogeneity?
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A new mutation will NOT affect siblings or their offspring (nieces, nephews) of the affected individual but THEIR OWN offspring are at risk for acquiring the new mutation.
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What might be asked regarding NEW mutations on a pedigree in the USMLE?
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When the severity of a disease worsens or age of onset of disease is earlier in succeeding generations....caused by triplet repeat expansion.
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What is anticipation?
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Try Hunting MY FRIED Eggs (X) TRI-nucleotide Huntington's Myotonic Dystrophy Friedrichs ataxia Fragile X
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What are the 4 most commonly cited diseased that involve triplet repeat expansion?
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Manifestation of TWO DIFFERENT DISEASES depending on whether the chromosome or gene deleted came from the mother or the father.
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How will imprinting likely show up on the USMLE?
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When differences in phenotype depend on whether the mutation came from maternal or paternal origin...This is completely normal, until the gene that was not turned off gets deleted. Then there is absence of the gene from say the father, but the maternal gene was imprinted and turned off by methylation....no good copies are left.
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What is Imprinting?
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PraderWilli---Deletion of normally active Paternal gene AngelMan Syndrome--Deletion of normally active Maternal gene
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What two genetic diseases are classic examples of imprinting defects?
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Ch 15
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On which chromosome does deletion occur that leads to PW or Angelman Syndrome?
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MR Hyperphagia and Obesity Hypogonadism Hypotonia
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What are the S/S of Prader Willi syndrome?
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MR Seizures Ataxia Inappropriate laughter (Happy Puppet)
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What are the S/S of AngelMan Syndrome
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When an offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent---can also be a cause of PW or Angelman syndrome.
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What is Uniparental disomy?
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Hypophosphatemic Rickets... (AKA vitamin D resistant rickets) Results in increased phosphate wasting at the Proximal tubule
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What is an example of an X-linked dominant disease?
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Leber's hereditary Optic neuropathy.--- Degeneration of retinal ganglion cells and axons leading to acute loss of central vision... not enuf ATP made by mitochondria to support the optic nerve.
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What disease is an example of Mitochondrial inheritance?
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P squared + 2PQ + Q Squared =1
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What is the Hardy-Weinberg Equation?
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The frequency of allele 1 (P) and allele 2(Q)
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What do P and Q stand for in the HQ equation?
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The frequency of genotype allele 1 and allele1 2pq is frequency of genotype allele 1 and allele 2 (heterzogote prevalaence) etc...
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What is Psquared in the HQ equilibrium?
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Chromosomal abnormality
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Most common cause of loss of pregnancy?
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When a cell has a multiple number of 23 chromosomes...46, 69 92...
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What is Euploidy?
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One that has 1 member of each chromosome.
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What is a haploid cell?
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One that has 2 copies of each pair of chromosomes
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What is a diploid cell?
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No
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Are triploidy or tetraploidy compatible with life?
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A cell having extra or missing chromosomes that are not a multiple of 23
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What is aneuploidy?
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YES
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Are all autosomal monosomies lethal?
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Trisomy 13, 18 and 21...three copies of 13, 18 or 21 respectively
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Which trisomies are compatible with life?
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XXY or XXXY
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What is the karyotype of Kleinfelter syndromes?
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When there are two different cell types within one persons body.... Say when half of the cells of a body are normal, and half have XXY, or half have 3 copies of Ch21.
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What is the idea of mosaicism?
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Nondisjunction during meiosis either 1 or 2.
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What is the most common cause aneuploidy?
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Because before that time, the risk of termination of pregnancy by amniocentesis is 1/200 but the risk if a generic disease is not, so amniocentesis is not generally done. After that age, the risk of a disease IS greater than 1/200 so amniocentesis is a good option.
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Why is an 'older mother' defined as being 35 or older?
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When two non-homologous chromosomes exchange genetic information--- 9:22, 8:14 etc.
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What is a reciprocal translocation?
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A Robertsonian Translocation has likely occurred in one of the parents germ cells...When these cells pair up in ADJACENT segregation, one of the sets is likely to have 1 normal Ch21 and another Ch with partial Ch21 material on it.
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On USMLE, what is the likely reason that a couple might have had multiple pregnancy losses and a Down Syndrome Child?
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When there is non-reciprocal chromosomal translocations of acrocentric chromosomes 13, 14, 15, 21 or 22. The small p arms of two chromosomes get broken off and disappear, the remaining q arms get joined together.
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What is a Robertsonian Translocation?
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Alternative segregation
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What type of chromosomal segregation can occur in Robertsonian or reciprocal translocations that still cause normal offspring when paired up?
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Interstitial deletion of part of the chromosome (in the middle portion of the chromosome) in addition to the normal imprinting.
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What type of DELETION occurs in Prader WIlli or Angelman syndromes?
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A terminal deletion of the short arm, p arm of chromosome 5
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What type of deletion occurs in Cri-du-chat syndrome?
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Microcephaly Moderate to Severe MR Epicanthal folds Cardiac Abnormalities CRY_DU_CHAT
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What are the findings of a Cri-du-Chat patient?
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Via nondysjunction followed by fertilization of a egg missing an X chromosome OR if the X chromosome becomes a RING chromosome, and then is lost from the cell
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What are two ways Turner Syndrome can come about?
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When the middle portion of a chromosome, including the centromere, is broken off, inverted and place back within the chromosome...Proceeds thru meiosis
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What is a Pericentric chromosomal inversion?
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When the end piece of a chromosome, not including the centromere, is broken off, inverted and placed back on the chromosome...Does NOT proceed thru meiosis.
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What is a paracentric chromosomal inversion?
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When instead of meiosis causing separation of two chromatids vertically to give 1 sister chromatid to each cell, they divide horizontally, leading to 2 q arms and 2 p arms being stuck to eachother.
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What is an isochromosome?
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P + Q=1 Allele P plus Allele Q must equal 1, the total of 100% of alleles.
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What is the equation for allele prevalence in terms of Hardy-Weinberg?
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2pq
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What represents the heterozygote prevalence in Hardy Weinberg Equation?
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q...normally it would be q squared (as it is for females) but if you are a male and you have the recessive x-linked gene, you have the disease.
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What is the prevalence of an X-linked disorder in males?
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Random Mating No migration No mutation No selection for any of the genotype loci
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What are the four things the Hardy-Weinberg equalibrium assumes?
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That P is approx = to 1 because q is always so so small (ie 1/10,000) 2pq equaling the carriers becomes 2q
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What can generally be assumed when calculating carrier risk or affected individuals (usually in AR diseases) using HW equation?
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When neither of two alleles is dominant...think blood groups
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What is codominance?
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Tendency for certain alleles at 2 linked loci to occur together more often than expected by chance...Varies between populations.
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What is linkage disequalibrium?
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When a mutation exerts a dominant effect, as in a heterozygote produces a nonfuntional altered protein that also prevents normal gene expression
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What is a dominant negative mutation?
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Deletion of the long arm, q arm of chromosome 7, which includes the elastin gene.
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What is the chromosomal defect in Williams Syndrome?
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Elfin faces Well developed verbal skills Cheerful disposition and friendliness with strangers MR CV problems
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What are the clinical manifestations of Williams Syndrome?
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22q11 deletion-- CATCH 22! Cardiac abnormalities Abnormal Facies Thymic aplasia Cleft palate Hypocalcemia
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What is the defect in DiGeorges Syndrome and what are the complications?
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A 22q11 microdeletion syndrome with palate, facial and cardiac defects.
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What is Velocardiofacial syndrome?
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CAG on Ch 4
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What Triplet repeat is seen in Huntingtons?
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CTG
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What triplet repeat is seen in MyoTonic dystrophy?
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CGG
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What triplet repeat is seen in FraGile X syndrome?
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CAA
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What Triplet repeat is seen in Friedrichs Ataxia?
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Increased nuchal translucency
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What does ultrasound show in a Down syndrome fetus?
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Increased B-hCH Increased Inhibit A Decreased AFP Decreased Estriol
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What are the results of a pregnancy quad screen on a Down syndrome fetus?
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Down Syndrome
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What is the most common cause of congenital mental retardation?
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MR Flat facies with epicanthal folds Simean Crease Gap between 1st two toes Duodenal atresia* Heart disease, usually ASD septum primum
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What are the common findings in a Down syndrome Baby?
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Alzheimers and ALL
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What diseases are Down syndrome babies at increased risk of acquiring?
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18, Edwards syndrome. 18= Election age
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What is the most common trisomy after 21?
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Micrognathia (small jaw) Clenched hands Rocker Bottom Feet Low set ears
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What are the findings of Edwards Syndrome ?
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PolyDactyly HoloProsencephaly Cleft lip or Palate Microcephaly and micropthalmia
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What are the clinical findings of Patau Syndrome?
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The PROTO oncogene is usually related to causing cell growth. A mutation in this gene leads to an oncogene, which is typically a GAIN IN FUNCTION of the proliferation gene Only ONE hit is necessary to mutate a protooncogene
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What are the general features of a proto-oncogene WRT causing cancer?
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Normal version of the gene is normally responsible for slowing down cell growth, ie p53. Mutation in this gene usually leads to a LOSS OF FUNCTION Two hits on the gene are necessary to mutate is enuf to cause cancer
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What are the general features of a Tumor Suppressor gene WRT causing cancer?
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Rb---Retinoblastoma BRCA 1 or 2--Breast Cancer p53--Li Fraumeni (multiple cancers) p16- Melanoma APC-Colon cancer
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Name 5 genes that are tumor suppressor genes that can be inherited with one abnormal copy of a gene, after which another mutation causes cancer.
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ApoE Presenillin Beta-Amyloid Precursor Protein (BAPP)
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What are three genes that are known to be mutated to cause Alzheimer's disease?
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Restriction Fragment Length Polymorphism-- Restriction endonucleases can cut a piece of DNA in various spots, and depending on the polymorphisms in different genes the fragments that are cut will be of different lengths---Southern blot to analyze
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What is the idea behind RFLP?
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Variable number of tandem repeats... There are variations in the number of repeats of a repeated sequence, and when these are cut by restriction endonucleases we can analyze them.
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What is the idea behind VNTR?
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Same as with VNTR, although the repeat sequences are often just several bases long repeated over and over.
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What is the idea behind STR analysis?
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Single nucleotide polymorphism.. DNA can be analyzed base on a single difference in a nucleotide sequence.
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What is the idea behind SNP analysis?
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That when crossing over occurs, there is less than 50% recombination between two gene....These tend to travel together in inheritance from mother or father to child.
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What does it mean when two genes are 'linked?'
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It is 1 million base pairs and It represents 1 percent recombination... A gene with 17% recombination is therefore 17 million base pairs apart.
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What is ONE CENTIMORGAN WRT linkage analysis?
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A logarithm of the Odds----an estimation by a computer as to whether or not two genes are linked. If LOD > 3 then two genes are linked. LOD <-2 then NOT linked...If between these values not enuf data is available.
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What is the LOD score?
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It represents the recombination frequency of two genes if the LOD score says they are linked.... Look for the HIGHERST LOD score and the corresponding Theta value.
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What is Theta WRT a LOD score?
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An allele specific oligonucleotide test...Used in direct DNA analysis when looking at the mutated gene directly. Involves synthesizing a strip of DNA that will base pair exactly with the gene being studied.
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What is an ASO test?
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CGG repeat... X-tra large testes, jaws and ears Autism...
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What are the clinical findings of Fragile X syndrome?
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Fragile X
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What is the second most common cause of Genetic MR after Downs?
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FMR1 gene....X-linked defect affecting the genes methylation Associated with chromosome breakage
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What is the gene associated with Fragile X syndrome?
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Increased CPK in blood and look at a muscle biopsy.
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How are muscular dystrophies diagnosed?
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Frame shift deletion of the dystrophin gene, leading to accelerated muscle breakdown esp in pelvic girdle
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What gene is affected in Duchenne muscular dystrophy?
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Duchennes MD... hypertrophy due to fibrofatty replacement of muscle
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What disease is associated with pseudohypertrophy of calf muscles?
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Duchennes MD...it involves the use of the upper limbs to stand up
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What is the GOWERs maneuver associated with?
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A X-linked disease caused by a mutated dystrophin gene...Less sever than Duchenne's
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What is Becker's MD?
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Be Wise, Fool's GOLD Heeds False Hopes Bruton's Agammaglobulinemia Wiskot Aldrich Fragile X G6PD Ocular Albinism Lesch Nyhan Duchenne and Becker MD Hemophilia A and B Fabry disease Hunter's syndrome
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What is a mnemonic to remember X-linked disorders?
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Cystic Fibrosis
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What is the most common lethal genetic disease of Caucasians?
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AR
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In what manner is CF inherited?
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CFTR gene Ch 7 Deletion of a Phe residue at position 508---Normal CFTR allows Cl- to flow into the lungs/GI tract and reabsorbs Cl- from sweat.
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What is the gene defective on CF, where is it located and how is it altered?
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Meconium ileus Pancreatic insufficiency Bronchiectasis and chronic bronchitis Often have Pseudomonas and S. aureas lung infections
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What are common signs or associations of patients with CF?
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Albinism A1AT deficiency ARPKD Glycogen storage diseases All lysosomal storage disease except Fabry All Mucopolysaccharidoses except Hunter's Thalassemias SCA PKU Hemochromatosis
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Name several AR recessive disorders.
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AD Defect in fibroblastic growth factor receptor 3
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What is the Mode of inheritance and what gene is affected in Achondroplasia?
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Dwarfism with short limbs Head and trunk are normal size (associated with increased paternal age)
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What are the clinical manifestations of Achondroplasia?
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AD Mutation is APKD1 gene on ch 16.. 16 letters in polycystic disease
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What is the Mode of inheritance and what gene is affected in APKD?
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Bilateral massive enlargement of the kidneys. Flank pain, hematuria, and renal failure
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What are the manifestations of APKD?
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Polycystic liver Mitral Valve prolapse Berry aneurisms
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What disease conditions are associated with APKD?
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AD APC gene deletion on Ch 5---5 letters in polyp
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What is the Mode of inheritance and what gene is affected in Familial Adenomatous polyposis?
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Schtuffpile of polyps on the colon, which will eventually become cancerous unless resected.
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Clinical manifestations of FAP?
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AD Defective or absent LDL receptor gene
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What is the Mode of inheritance and what gene is affected in Familial Hypercholesterolemia IIa
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Elevated LDL....Severe atherosclerosis in early life, including tendon xanthomas, esp of the Achilles tendon.
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What are the clinical manifestations of Familial Hypercholestrolemia IIa?
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AD...Inherited disorder of BVs
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What is the Mode of inheritance in Hereditary hemorrhagic telangiectasia?
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AD---defect in ankyrin or spectrin or band 3
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What is the Mode of inheritance and what gene is affected in Hereditary Spherocytosis?
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Spherocytes, increased MCHC and hemolytic anemia
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Findings in a blood smear of a pt with Hereditary spherocytosis?
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AD CAG trinucleotide repeat seen due to damage on Ch 4---Think Hunting 4 food.
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What is the Mode of inheritance and what gene is affected in Huntington's disease?
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Progressive dementia Choreiform movements Caudate atrophy.... Decreased GABA and Ach in the caudate and basal ganglia
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Clinical manifestations of Huntingtons?
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AD-- Fibrillin gene on Ch 15
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What is the Mode of inheritance and what gene is affected in Marfans?
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AD ret gene
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In what manner are the MEN syndromes inherited and what is the gene involved in MEN II and III?
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AD Long arm of Ch 17... 17 letters in von Recklinghausen
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What is the Mode of inheritance and what gene is affected in Neurofibromatosis 1?
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Cafe-au-lait spots Neural tumors Lisch nodules (pigmented iris hamartomas) Scoliosis
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What are the clinical manifestations of NF1?
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Optic gliomas Pheochromocytoma Increased tumor susceptibility
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What other disease conditions are associated with NF1?
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AD Ch 22 think type 2 is 22
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What is the Mode of inheritance and what gene is affected in NF2?
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Bilateral acoustic neuromas Juvenile cataracts
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What are the clinical features of NF2?
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AD
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In what manner is Tuberous Sclerosis inherited?
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Ash Leaf spots (hypopigmented) Cortical and Retinal hamartomas Seizures and MR
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What are the Clinical Findings of Tuberous Sclerosis patients?
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Renal cysts Renal angiomyolypomas Cardiac rhabdomyomas Increased incidence of astrocytomas
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What are associated disease conditions seen in Tuberous Sclerosis patients?
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AD Deletion of the VHL gene, a tumor suppressor gene on Ch 3....von Hippel Lindau=3 words
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What is the Mode of inheritance and what gene is affected in von Hippel Lindau?
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Hemangioblastomas of retina, cerebellum and medulla Multiple bilateral renal cell carcinomas Multiple other tumors caused by increase in angiogenic growth factors
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What are the clinical findings of von Hippel Lindau patients?
