Genetics Exam 1 MBS

Card Set Information

Genetics Exam 1 MBS
2016-08-22 15:02:04

Exam 1, lectures 1-7
Show Answers:

  1. Lecture 1
  2. constitutional
    a change present at birth, in all or some cells
  3. congenital
    a change present at birth, often before birth
  4. acquired
    • a change that happens after birth, usually associated with cancer
    • •a change occurring in a subset of cells, NOT present at birth
  5. somatic
    occurring in the body, but not in the gametes, therefore can't be passed on to any offspring
  6. obligate carrier
    the parent of a child with a recessive condition
  7. dizygotic twins
    • boy & a girl
  8. monozygotic twins
    • same sex twins
  9. familial relations
  10. Lecture 2
  11. unit inheritance
    parental phenotypes do not blend; eg. if a parents who has dwarfism and a parent of regular height have a child the child's height won't be in between, it will be either regular or dwarf
  12. segregation
    genes occur in pairs; only on member of the pair is transmitted, or two members of a pair of genes segregate and pass to DIFFERENT gametes
  13. independent assortment
    genes at different loci are transmitted independently; there's a random recombination of maternal and maternal chromosomes in gametes
  14. autosomal dominant inheritance
    • • only one mutated copy is necessary for expression
    • • transmission is vertical (people of every generation are affected)
    • • there's male to male transmission
    • • males and females are equally affected
    • • disorder can arise as a de novo mutation
    • • if you don't HAVE the gene, then you won't pass it on
  15. name 4 autosomal dominant diseases:
    • 2) FH (familial hypercholesterolemia)
    • 3) postaxial polydactyly (extra pinky)
    • 4) Huntington's
  16. Achondroplasia
    • • most common form of short-limbed dwarfism
    • • 90% of the time neither of the parents are dwarfs and it's a new mutation
    • • gene = FGFR3
  17. variable expressivity
    family members may express symptoms of an autosomal dominant disorder to different degrees
  18. penetrance
    the proportion of people who carry a mutated gene of an autosomal dominant disorder who present with any of the known phenotypic (symptoms) of the gene
  19. penetrant
    a person has a gene mutation that is inherited in an autosomal dominant fashion and shows clinical expression (expresses the trait)
  20. incomplete/reduced penetrance
    the frequency of the phenotype is less than 100% in known heterozygotes
  21. non-penetrant
    a person has a gene mutation that is inherited in an autosomal dominant fashion but doesn't show any clinical expression
  22. advanced paternal age
    increases the risk for de novo mutations; the rate of new mutations increases due to increased number of divisions required to produce sperm throughout a lifetime
  23. autosomal recessive inheritance
    • • two mutated copies needed for expression
    • • both parents are carriers, generally clinically normal
    • • family history often negative
    • • equal number affected males and females
    • • consanguinity may be present
    • • may see ethnic predisposition
  24. name 2 autosomal recessive diseases:
    • 1) diastrophic dysplasia
    • 2) cystic fibrosis
  25. consanguinity
    term used if individuals are related by blood prior to marriage or mating
  26. Diastrophic Dysplasia
    • an autosomal recessive form of skeletal dysplasia
    • • short stature
    • • club foot
    • • cleft palate
    • • “hitchhiker’s thumb"
    • • “cauliflower ear”
    • • gene = DTDST
    • • associated with normal intelligence, Finnish ancestry
  27. name 1 X-linked recessive disease:
    1) duschenne muscular dystrophy (DMD)
  28. X-linked recessive inheritance
    • • no male to male transmission
    • • hemizygous males affected
    • • heterozygous females unaffected
    • • higher incidence in males than females
    • • carrier females may show variable expression due to lyonization
  29. Lyonization/the Lyon hypothesis
    in somatic cells of female mammals, only one X chromosomes is majorly active; inactivation occurs early in embryonic life and is random but FIXED
  30. X-Linked Recessive Disorders in Females (5)!!!!
    • 1) cells with unaffected X are inactivated in disproportionate numbers
    • 2) affected female has 45,X karyotype (Turner's, XO) and inherits the X chromosome containing mutation
    • 3) mutation resulting from X chromosome/autosome translocation; normal X chromosome is inactivated to preserve autosomal material; the translocation itself can cause a disruption/mutation in the gene
    • 4) affected female has an affected father and a carrier mother
    • 5) disorder is genetically heterogeneous (really AR, or not necessarily only x-linked recessive)
  31. Segregation of X-Linked Recessive Trait if Father is Affected
    All the daughters are carriers, none of the sons are affected
  32. X-Linked Dominant Inheritance
    • • more females affected than males
    • • sometimes lethal in males
    • • affected males have daughters that are ALWAYS affected, but no affected sons
    • • no male to male transmission
    • • affected females have 50% chance of passing gene on with each pregnancy
  33. name 2 X-linked dominant disease:
    • 1) Hypophosphatemia (vitamin D resistant rickets)
    • 2) Incontinentia Pigmenti (lethal in males)
  34. Anticipation
    the tendency of certain diseases to appear at earlier ages, with increased severity in successive generations
  35. Compound heterozygote
    two different abnormal alleles at one locus in one individual
  36. Dominant negative mutation
    mutation present in one copy, in which the abnormal gene product suppresses or destroys the normal gene product
  37. Gene locus
    the site on the chromosome at which a gene is located
  38. Mitochondrial Inheritance
    • • when a father's affected, none of his children are affected
    • • when a mother is affected, ALL her children are affected to some degree
    • • some subunits are encoded by mitochondrial genes: these are inherited maternally and can lead to energy failure
    • • most proteins functioning in mitochondria are encoded by nuclear genes; when these genes are disrupted, the resulting condition is usually inherited in a autosomal recessive fashion
  39. Why are mitochondrial defects only passed maternally?
    sperm mitochondria degenerate upon penetration of the ovum; ovum contributes more cytoplasm to zygote than the sperm; mitochondria in offspring are exclusively maternal in origin; only mitochondria from oocyte contribute to zygote
  40. heteroplasmy
    mixture of normal and abnormal mtDNA within a cell or individual
  41. homoplasmy
    all mtDNA is the same (either normal or abnormal)
  42. threshold effect
    • a certain percentage of abnormal mtDNA will be tolerated without symptoms until a critical threshold is reached, then symptoms will appear
    • • threshold can differ among individuals, even among different tissues in same individual
    • • over time, more organ systems can be affected, as more tissues exceed the threshold
  43. Why would one type of mtDNA have a replicative advantage over another?
    A smaller mtDNA might arise because of a deletion, replicate faster than a normal, full length mtDNA, therefore gradually increase its load over time
  44. random drift
  45. replicative segregation
    • mitochondria are partitioned along with the cytoplasm during cell division; distribution of mutant and normal molecules in the daughter cells of heteroplasmic cell may be unequal; in course of development and differentiation, different parts of the body may have different proportion of mutant molecules
    • -selective advantage
    • -genetic drift
  46. What kind of tissues are likely to be affected in mitochondrial disorders?
    Tissues with high energy requirements like the brain, skeletal muscle, heart muscle, smooth muscle
  47. How would you go about diagnosing a mitochondrial disorder?
    a muscle biopsy is performed to measure enzyme function and analyze mtDNA
  48. Is prenatal diagnosis effective for mitochondrial disorders?
    it is theoretically possible but prognosis is difficult to predict because of heteroplasmy
  49. How can mothers avoid passing on mtDNA mutations to their offspring?
  50. name 4 autosomal dominant diseases:
    • 1) MELAS
    • 2) Leber’s Hereditary Optic Neuropathy
    • 3) Pearson syndrome
  51. Leber’s Hereditary Optic Neuropathy
    • • sudden, irreversible, usually bilateral, loss of vision leading to blindness due to optic nerve death
    • • HOMOPLASMIC point mutation within the mtDNA
  52. MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes)
    • • highly variable expression of stroke-like episodes with usually temporary neurologic changes, migraines, seizures, developmental delay, dementia, diabetes, deafness, myopathy, lactic acidosis
    • • HETEROPLASMIC point mutation with mtDNA
  53. Etiology
    the cause of a disease or condition
  54. Pleiotropy
    • a mutation in a single gene have more than one phenotypic effect on the body
    • • eg. mutations in the fibrillin gene are pleiotropic - they affect the heart, skeletal system, and eye
  55. heterogeneity
    a single phenotype may be caused by different mutations (contrast to pleiotropy, where mutation in a single gene may cause different phenotypes)
  56. Allelic heterogeneity
    • different mutations within a single gene locus cause the same phenotypic expression
    • -eg. there are over 1000 known mutant alleles of the CFTR gene that cause cystic fibrosis
  57. Locus heterogeneity
    • variations in completely unrelated gene loci cause a single disorder
    • -eg. retinitis pigmentosa has autosomal dominant, autosomal recessive, and X-linked origins, & only one mutant locus is needed for the phenotype to manifest
  58. Lecture 3
  59. Mosaicism
    presence of more than one cell line in an individual
  60. Somatic mosaicism
    caused by a post-zygotic mutation which affects a certain percentage of cells in an individual
  61. What are three examples of diseases caused by somatic mosaicism?
    • 1) Mosaic Down Syndrome
    • 2) Segmental Neurofibromatosis
    • 3) McCune-Albright Syndrome (ALWAYS MOSAIC, would be lethal otherwise)

    MA SfN DS
  62. Gonadal mosaicism
    presence of more than one cell line in the gonadal cells but not in the rest of the body
  63. Under what circumstances would a geneticist expect a condition to be caused by gonadal mosaicism?
    when unaffected parents have more than one child with an autosomal dominant disorder; if a child with an “apparently” new mutation had unaffected parents and a negative family history
  64. What is an example of a disease caused by gonadal mosaicism?
    OI (osteogenesis imperfect) or brittle bone disease; it's always caused by a de novo mutation
  65. Uniparental disomy (UPD)
    the presence of two homologous chromosomes inherited from only one parent, meaning that one parent has contributed two copies of a chromosome and the other parent has contributed NONE copies
  66. heterodisomy
    • non-disjunction in meiosis I occurs, resulting in a parent passing on one copy of each homolog
    • (meiosis I --> hetero)
  67. isodisomy
    • non-disjunction in meiosis II occurs, resulting in a parent passing ons two copies of the same chromosome
    • (meiosis II --> iso)
  68. What are the postulated mechanisms for uniparental disomy?
    • 1) trisomic conception with postzygotic loss of a chromosome
    • 2) fertilization of a nullisomic gamete by a disomic gamete (a gamete that's missing a copy of a chromosome joins with a gamete that has two copies)
    • 3) compensatory duplication of the chromosome in a monosomic cell
  69. trisomic conception
    if an oocyte or spermatocyte that has two copies of a chromosome is joined by sperm or oocyte with one chromosome in question, there are 3 copies of the chromosome, and the copy of the chromosome most likely to be lost is from the parent who only gave ONE
  70. nullisomic gamete
    a gamete that's missing a copy of a chromosome; a previous non-disjunciton event in the parent must have occurred to produce a gamete without a chromosome
  71. disomic gamete
    joins with a gamete that has two copies
  72. When is UPD clinically significant?
    when it involves chromosomes with imprinted genes or chromosomes containing an autosomal recessive (e.g. CF) mutation (isodisomy)
  73. Genomic Imprinting
    methylation aka silencing of maternal or paternal genes in the zygote; some genes are expressed preferentially in either the maternal or paternal genotype
  74. When can disorders result from genes that undergo genomic imprinting?
    if a patient has uniparental disomy or a heterozygous deletion for an imprinted region of a chromosome
  75. Prader-Willi
    • P for Paternal gene deletion on chromosome 15, or by uniparental maternal disomy of chromosome 15
    • • in a normal individual, the corresponding maternal gene is imprinted (& the paternal gene is expressed)
    • • therefore with no functional paternal copy of the gene, there is no expression--> disorder
    • • hypotonia, intellectual disability and obesity
  76. Angelman Syndromes
    • Angel--> feminine--> Maternal gene deletion on chromosome 15, or by uniparental paternal disomy of chromosome 15
    • • in a normal individual, the corresponding paternal gene is imprinted (& the maternal gene is expressed)
    • • therefore with no functional maternal copy of the gene, there is no expression--> disorder
    • • severe intellectual disability, movement disorder and seizures
  77. Trinucleotide Repeat Disorders (anticipation)
    in families affected by triplet repeat disorders, the area is unstable, leading to progressive amplification of the gene sequence with each succeeding generation
  78. What are 3 examples of triplet repeat disorders?
    • 1) Myotonic Dystrophy
    • 2) Fragile X Syndrome
    • 3) Huntington Disease
  79. Fragile X Syndrome
    • • most common form of inherited intellectual disability
    • • expansion from pre to full mutation ONLY occurs through FEMALE meiosis
    • • X-linked semi-dominant
    • • a normal males' daughters meiosis replication is UNSTABLE
  80. Myotonic Dystrophy
    • • autosomal dominant disease showing anticipation
    • • congenital form occurs from maternal transmission only
  81. Huntington Disease
    • • autosomal dominant disorder (often w/out anticipation)
    • • occasional juvenile-onset - always paternal transmission
    • • progressive involuntary movements, cognitive loss, leading to complete debilitation; psychiatric problems
  82. Lecture 4
  83. Single base substitutions: missense, nonsense, & splice site
    • missense mutations: replace one amino acid with another in the gene product
    • nonsense mutations: replace an amino acid with a stop codon
    • splice site mutations: create or destroy signals for exon/intron splicing
  84. microdeletions
    a constellation of findings due to a specific large deletion including several genes (eg. Williams syndrome)
  85. Insertions
    mutations that result in extra DNA sequence within the coding sequence of a gene
  86. Frameshifts
    produced by deletions, insertions or splicing errors resulting in the shift of the reading frame; they often result in a stop codon that produces a truncated polypeptide
  87. Promoters
    those that affect the binding of RNA polymerase to the promoter site, which can result in the reduced production of mRNA and therefore decreased production of a protein
  88. Duplications
    type of insertion that are due to repeated regions of DNA, often including whole genes; regions can be duplicated next to one another (end to end) or elsewhere on the genome
  89. Tandem repeat expansions
    when repeats increase from small to large number genetic diseases occur; further expansion of the repeat sequences can lead to more severe disease in the patient’s offspring (anticipation); eg. Fragile X, Huntington’s disease, and myotonic dystrophy are triplet repeat disorders
  90. Loss of Function Mutation (3)
    • mutations result in gene products that have reduced function, no function, and/or may interfere with the function of the normal product
    • 1) null mutations
    • 2) dosage effects
    • 3) dominant negative
  91. Null Mutation
    • • often inherited in an AR manner
    • • 50% function is sufficient: carriers are healthy
    • • if two mutated copies are passed on the child will be diseased
  92. Dosage effect/Incomplete Dominance/
    • • mild disease inherited in an AD manner
    • • severe disease inherited in an AR manner
    • • conditions for which you need more than 50% function be to completely healthy
  93. Codominance
    single gene has more than one dominant allele; an individual who is heterozygous for two codominant alleles will express the phenotypes associated with both alleles
  94. Haploinsufficiency
    occurs when a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation) and the single functional copy does not produce enough of a gene product (typically a protein) to bring about a wild-type condition, leading to an abnormal or diseased state
  95. Dominant Negative:
    • • useless and gets in the way
    • • disease inherited in an AD manner
    • • mutant protein doesn't do its job and interferes with normal protein produced by the unmutated allele  
  96. Gain of function Mutations
    • cause the protein product to actively function in a new, abnormal way
    • • disease inherited in an AD manner (can be inherited or de novo)
    • • eg. Achondroplasia caused by mutation in the FGFR3 gene that causes receptor to be constantly on resulting in poor bone growth
  97. Benefits of DNA-based tests (4):
    • a) Definitive diagnosis: Clinical diagnosis of a genetic disease can be confirmed by molecular analysis
    • b) Presymptomatic diagnosis: Individuals at risk for disease can be identified before the disease has become clinically evident allowing use of prophylactic measures for screening and treatment.
    • c) Preimplantation or prenatal diagnosis: Allows for diagnosis of genetic conditions with known mutations in a blastocyst or fetus.
    • d) Genotype-phenotype correlations: Identification of certain mutant alleles may help predict specific prognosis, clinical phenotype, or therapeutic response.
  98. Challenges of DNA-based tests (5):
    • a) Heterogeneity: Mutations in several different genes may produce the same clinical syndrome.
    • b) Allelic disorders: Different mutations in the same gene may produce different clinical syndromes.
    • c) Variable expression: Genetic diseases may be variable within families and between families (knowing the mutation does not necessarily predict phenotype)
    • d) Non-paternity can be inadvertently exposed
    • e) Genetic discrimination concerns may arise
  99. Methylation Specific RT-PCR
    treatment of DNA with bisulfite converts cytosine residues to uracil, but leaves 5-methylcytosine residues unaffected; can tell what parts of genome are or aren't silenced
  100. direct sequencing
    this technique is used to look for disease causing mutations within a given gene
  101. Allele specific oligonucleotide testing (ASO)
    commonly used to look for a panel of common mutations in a given gene or several genes; an ASO is a short piece of synthetic DNA complementary to the sequence of a variable target DNA. It acts as a probe for the presence of the target in a Southern blot assay.
  102. multiple ligation-dependent probe amplification
    multiple eons can be amplified at once and run out on a gel to determine presence of region
  103. Short tandem repeat (STR) analysis
    compares specific loci on DNA from two or more samples; measures the exact number of repeating units; probes are attached to desired regions on the DNA, and a polymerase chain reaction (PCR) is employed to discover the lengths of the short tandem repeats
  104. screening
    the process of looking for mutations in someone who is at higher than usual risk for a disease or a disease predisposition, but is not yet affected
  105. Testing
    the process of targeted disease-specific laboratory procedures to show that someone is definitively affected or not affected with a disease
  106. Specific populations are predisposed to certain diseases. By providing genetic screening preconceptionally or early in pregnancy, people are provided important information to use when planning or considering pregnancy options.
  107. Southeast Asian, Italian, Greek predisposed to:
  108. French Canadian predisposed to:
    tyrosinemia, Tay-Sachs, Usher syndrome
  109. Ashkenazi Jewish predisposed to:
    • Tay-Sachs, Gaucher, Canavan disease, Niemann Pick type A,
    • mucolipidosis IV, familial dysautonomia, Bloom syndrome, Fanconi anemia type C, cystic fibrosis, glycogen storage disease IA, maple syrup urine disease, Usher syndromes IF and III, nemaline myopathy, hyperinsulinemia, dehydrolipoamide dehydrogenase deficiency, Joubert, Walker-Warburg
  110. African predisposed to:
    thalassemia, sickle cell anemia, hemoglobin C
  111. All populations predisposed to:
    cystic fibrosis, spinal muscular atrophy
  112. Lecture 5
  113. Ploidy
    one set of 23 chromosomes; normal is diploid = 46
  114. Polyploidy
    • abnormality in number of all chromosomes
    • •triploidy - having 3 full sets of chromosomes (69,XXY)
    • •tetraploidy - having 4 full sets of chromosomes (92,XXYY)
  115. Mosaic
    more than one cell line or karyotype present
  116. Autosome
    chromosomes 1 – 22 (non-sex chromosomes)
  117. Diploid
    normal chromosome number of 46 (two copies of each chromosome)
  118. Monosomy
    • loss of a chromosome, total number of chromosomes = 45
    • •eg. Turner's Syndrome
  119. Trisomy
    gain of a chromosome; total number of chromosomes = 47
  120. Triploidy
    gain of a whole set of 23 chromosomes; number of chromosomes = 69
  121. in cytogenetics looking for changes in:
  122. What are constitutional prenatal indicators a karyotype analysis should be conducted?
    • •advanced maternal age
    • •ultrasound abnormalities
    • •abnormal screening test
  123. What are constitutional perinatal (period around childbirth) indicators a karyotype analysis should be conducted?
    • •confirmation of a clinical diagnosis
    • •ambiguous genitalia
    • •multiple congenital dysmorphic features
  124. What are constitutional indicators in childhood a karyotype analysis should be conducted?
    • •short stature
    • •developmental delay
  125. What are constitutional indicators in adulthood a karyotype analysis should be conducted?
    •history of pregnancy loss
  126. What is the only acquired indicator for a karyotype analysis?
    • hematological malignancy: cancer that affects blood, bone marrow, & lymph nodes
    • • can be an indicator for a child or an adult
  127. What is the difference between a numerical constitutional change and a structural constitutional change?
    • • A numerical constitutional change is the gain or loss of a chromosome
    • • A structural constitutional change is a translocation, deletion, duplication, inversion or insertion of chromosomal material
  128. most frequent liveborn trisomies (6):
    • 13 (Patau Syndrome)
    • 18 (Edwards Syndrome)
    • 21 (Down Syndrome)
    • Turner Syndrome
    • Klinefelter Syndrome
    • Triple X syndrome
    • •ALL OTHER TRISOMIES are associated with infertility or pregnancy loss
  129. How does the size of the chromosome which is part of the trisomy affect the phenotypic condition?
    the larger the chromosome, the worse the outcome of having an extra one
  130. Patau Syndrome (Trisomy 13) Features
    • •Scalp defects (cutis aplasia, absence of skin)
    • •microphthalmia: very small or poorly developed eyes
    • •Polydactyly: extra fingers or toes
    • •microcephaly: small head
    • •holoprosencephaly (embryo forebrain fails to develop into two hemispheres)
    • •cleft lip: opening in the lip
    • •cleft palate: opening in the roof of the mouth
    • •CHD-heart defects
    • •very poor prognosis (5% survive 6 months)
  131. Edwards Syndrome (Trisomy 18) Features
    • •rocker bottom feet
    • •small, abnormally shaped head
    • •small jaw and mouth
    • •clenched fists w/ overlapping fingers
    • •congenital heart defects
    • •Small size, small head circumference
    • •very poor prognosis, only 5% survive beyond 1 year
  132. Down Syndrome (Trisomy 21) Features
    • •flat facial profile
    • •upslanted palpebral fissures
    • •abnormal auricles (outer portion of ear)
    • •nuchal skin fold (thickness of the skin around the neck)
    • •single palmar crease
    • •clinodactyly (pinkie finger curved)
    • •hypotonia (floppy)
    • •hyperflexibility of joints
    • •intellectual disability
    • •leukemia
  133. Turner Syndrome (45 X) Features
    • •short stature
    • •puffiness or swelling (lymphedema) of the hands & feet
    • •loss of ovarian function
    • •affected girls do not undergo puberty
    • •infertility
    • •extra folds of skin on the neck (webbed neck)
    • •low hairline at the back of the neck
    • •skeletal abnormalities
    • •horseshoe kidney
    • •widely-spaced hypoplastic (underdeveloped) nipples
  134. Klinefelter Syndrome Features (XXY)
    • •tall stature, long limbs
    • •learning disabilities
    • •gynecomastia (breast enlargement)
    • •small testes
    • •infertility
    • •(low testosterone, micropenis, reduced facial/body hair)
  135. Triple X Syndrome (47,XXX) Features
    • •Speech delay
    • •IQ 10-15 points below siblings
    • •Increased risk for infertility
    • •Most offspring are chromosomally normal
  136. 47,XYY Males: Features
    • •IQ 10-15 points below siblings
    • •May be at increased risk for behavioral problems - impulsivity & emotional immaturity
    • •Most offspring are chromosomally normal
  137. Non-disjunction
    failure of chromosomes or chromatids to separate and go to different daughter cells
  138. Triploidy most often results from:
    • •two sperm fertilizing one egg
    • •it's frequently seen in missed abortion material
  139. Lecture 6
  140. What's the difference between distal and proximal in terms of chromosomal breaks?
    • •Distal = on (closer to) the telomeric side of a break
    • •Proximal = on (closer to) the centromeric side of a break
  141. Deletions on which chromosomes exhibit syndromes? (7)
    - 4, 5, 8, 13, 15, 17, & 18
  142. Cri-du-chat Syndrome (5p-syndrome)
    • caused by a deletion of the terminal part of chromosome 5
    • • can detect using cytogenetics or FISH
  143. What are the symptoms of Cri-du-chat Syndrome?
    • • microcephaly (smaller head)
    • • widely spaced eyes
    • • pointy ears
    • • seizures
    • • developmental and behavioral problems
  144. Microdeletion syndromes
    • Often result of submicroscopic deletion of more than one gene from chromosome
    • • deletion is too small to be seen by conventional karyotype analysis
    • • often need FISH to detect
  145. Examples of Microdeletion syndromes (5):
    • • 7: Williams (elastin gene deleted)
    • • 15: Angelman
    • • 15: Prader Willi
    • • 17: Miller-Dieker (lissencephaly)
    • • 22: Velo-Cardio-Facial/DiGeorge
  146. What test can be used to screen people for deletions (microdeletions) or duplications too small to be detected by a conventional karyotype?
    • a comparative Genomic Hybridization (CGH) by microarray
    • • can test known syndromes caused by deletions/duplications of chromosome in one single sample
    • • microarray will screen entire genome for deletions/duplications too small to be detected by conventional karyotype
  147. Deletions (loss of material) tend to result in:
    a MORE severe phenotype than duplication of material (most deletions are small, less than one chromosome band)
  148. DiGeorge/VCFS Syndrome
    • • chromosome 22 microdeletion
    • -born with cleft palates & heart disease
    • -immune dysfunction
    • -abnormal kidneys
    • -learning disabilities
  149. Miller-Dieker Syndrome
    • •chromosome 17 microdeletion
    • •lissencephaly: lack of development of brain folds/grooves
    • •vertical forehead crease
  150. Williams Syndrome
    microdeletion of elastin gene on chromosome 7
  151. Infertility
    a year of unprotected sex with no conception
  152. Translocations
    exchange of material between two or more chromosomes; can be balanced or or unbalanced
  153. unbalanced
    this type of translocation has a combination of monosomy & trisomy
  154. derivative chromosome
    • in regard to a translocation refers to the structurally rearranged chromosome
    • • this is the chromosome that HAS a deletion [monosomy] (and usually 'extra' part of the other chromosome with which the translocation occurred)
  155. notation example of an unbalanced translocation:
    • 46,XX,der(8)t(1;8)(p22;q24)
    • • notates BOTH der [derivative chromosome] & t [translocation] --> abnormal
    • *someone with a balanced translocation is at risk for having a fetus with an UNbalanced translocation b/c his or her two derivative chromosomes could go to different daughter cells in meiosis
  156. notation example of an balanced translocation:
    • 46,XX,t(1;8)(p22;q24)
    • • only notates the t [translocation]
  157. q = ___________ and p = ___________
    q = the long arm and p = the short arm
  158. 46,XY,t(3;5)(q21;p13)
    • there is a balanced translocation between chromosomes 3 & 5; 3 was broken in the long arm (place 21) and now has 5's part of the short arm 13 there; 5 was broken in the short arm (place 13) and now has part of 3's long arm there
  159. 46,XX,der(3)t(3;5)(q21;p13)
    • unbalanced translocation showing chromosome 3 broke in the long arm at position 21, and now contains chromosome 5's short arm 13 segment there
  160. 46,XY,der(5)t(3;5)(q21;p13)
    • unbalanced translocation showing chromosomes 5 broke at position 13 on the short arm, and now contains some of the long arm of chromosome 3 at the break instead
  161. Robertsonian translocations
    • when there is a non-critical loss of genes in the short (p) arm) regions of the chromosomes involved
    • • participating chromosomes break at centromeres and long arms fuse to form a single chromosome with a single centromere
    • • short arms also join to form a reciprocal product: this usually contains nonessential genes & is lost within a few cell divisions
  162. Robertsonian translocation notation:
    • 45,XX,der(13;14)(q10;q10)
    • • 45 is NORMAL in Robertsonian (46 is NOT)
    • • q10 means the break is in the centromere & the long arm is present
  163. acrocentric chromosome
    chromosomes 13, 14, 15, 21, & 22 have p arms that contain genetic material (eg. repeated sequences such as nucleolar organizing regions) that can be lost without causing significant harm
  164. how Robertsonian translocation can result in trisomy during conception:
    • 46,XX,der(14;21)(q10;q10),+21
    • • a child inherits the translocated chromosome from one parent in addition to two normal copies from the other
  165. Philadelphia translocation
    balanced between 9 and 22; seen in chronic myeloid leukemia (CML)
  166. Chronic myelogenous leukemia (CML)
    • • increased + unregulated growth of myeloid cells in bone marrow --> accumulation of these cells in the blood
    • • cellular oncogene activation because of chromosomal translocation in stem cells between the long arms of chromosomes 9 and 22 (Ph [philadelphia chromosome])
  167. BCR-ABL fusion gene
    • a tyrosine kinase that activates a cascade of proteins that speed up cell division & inhibits DNA repair,
    • • this makes the gene susceptible to further damaging mutations
    • • abl oncogene = on chromosome 9
    • • breakpoint cluster region = on chromosome 22
  168. clonal evolution
    • additional karyotype changes (mutations) in an individual; usually occurs when there is disease progression
    • • as changes get more complex, unbalanced translocations become more frequent
    • •* these only affect cells in the bone marrow & patient’s phenotype is unchanged
  169. How are acquired translocations frequently confirmed and monitored?
    • FISH
    • • eg. the t(9;22), the probes span the breakpoints of ABL on 9 (red) and BCR on 22 (green)
    • • exchange of material brings red signal and green signal together [on der(9) & der(22)] --> two yellow signals
    • • requirement of two yellow signals reduces the false positive rate.
  170. Lecture 7
  171. Birth Defect
    • condition present at birth which requires medical, surgical or cosmetic intervention
    • • eg. congenital heart disease, polydactyly, neural tube defect
  172. Dysmorphic Features
    • variants of physical features that exist in less than 2-3 % of the general population
    • •eg. single transverse palmar crease
    • •THREE OR MORE dysmorphic features/minor anomalies correlate with a possible genetic syndrome
  173. Syndrome
    pattern of multiple anomalies thought to be pathogenically related (eg. Down, Neurofibromatosis type 1)
  174. valuation for mild dysmorphic features
    • –features found in a relatively small percentage of the entire population
    • – or features which have been found to occur more commonly in genetic syndromes
    • - 3 or more dysmorphic features / minor anomalies strongly correlate with a possible genetic syndrome
  175. Syndrome
    a recognizable pattern of multiple anomalies thought to be pathogenetically related
  176. Association
    nonrandom occurrence in two or more individuals of multiple anomalies; etiology unknown
  177. VACTERL (VATER) Association
    • • V: vertebral
    • • A: anal anomalies
    • • C: cardiac
    • • TE: tracheo-esophageal fistula
    • • R: renal anomalies
    • • L: limb anomalies
  178. CHARGE
    • • used to be an associate, now it's a SYNDROME; helices binding protein
    • • C: colobomas (hole) of the eye
    • • H: heart defects
    • • A: atresia choanae (nAsal passage blockage)
    • • R: retarded growth and development
    • • G: genital hypoplasia (underdevelopment)
    • • E: ear anomalies including hearing loss
  179. Sequence
    • a pattern of multiple anomalies derived from a single mechanical factor
    • • Pierre Robin sequence: tongue falls back and obstructs airway
    • • Potter sequence: not enough amniotic fluid
  180. Potter Sequence
    • patten of findings due to not enough amniotic fluid (SEQUENCES because it's caused by a mechanical factor)
    • -fetus has abnormal kidneys
    • -flat facial features
    • -lungs don't develop normally b/c fetus can't breath in amniotic fluid
    • -babies pass away due to abnormal lung development
  181. malformation
    morphologic defect resulting from an intrinsically abnormal developmental process (the program wasn't correct to start with)
  182. What's an example of a malformation?
    • 1) cleft palate
    • 2) webbed digits
  183. deformation:
    • an abnormal form or position of a part of the body caused by MECHANICAL, non-disruptive forces
    • eg. foot binding
  184. What are two types of deformations?
    • 1) congenital dislocation of the hip (happens during breached birth)
    • 2) clubfoot
  185. Disruption
    a defect resulting from a breakdown of, or interference with, an originally normal developmental process
  186. What's an example of a disruption?
    amniotic band syndrome resulting in amputation of a finger
  187. Dysplasia
    • abnormal cellular organization or function within a specific tissue type throughout the body --> clinically apparent structural changes
    • eg. hemangioma or skeletal dysplasia such as osteogenesis imperfecta
  188. Teratogens can cause:
  189. Teratogens
    • substances encountered during pregnancy which can lead to birth defects; effect on the fetus is highly dependent on the gestational age at time of exposure and dose
    • • Infectious (rubella, syphilis, CMV, others)
    • • Medications (thalidomide, Accutane, antiepileptics)
    • • Drugs of abuse (cocaine, alcohol)
    • • External Agents (radiation, hyperthermia)
    • • Maternal Disorders (diabetes, lupus, PKU)
  190. Epistasis
    phenomenon in which the expression of one gene depends on the presence of one or more 'modifier genes'
  191. Phenocopies
    when a phenotype is seen as a result of environmental factors and genotype in separate cases
  192. Multifactorial inheritance
    many factors are involved in causing a birth defect