3 NonMendelian Genetics

  1. What is non-mendelian inheritance?
    any pattern of inheritance in which traits do not segregate in accordance with Mendel’s laws

    • includes Mitochondrial, Trinucleotide Repeats, Mosaicism, Genomic Imprinting (Uniparental Disomy), Multifactorial, Chromosomal
  2. 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

    • in general, TRs are present throughout the genome & are usually stable during mitosis & meiosis
  3. What are 3 examples of trinucleotide repeat disorders?
    • 1. Myotonic Dystrophy
    • 2. Fragile X Syndrome
    • 3. Huntington Disease
  4. Anticipation
    the tendency of certain diseases to appear at earlier ages with increased severity in successive generations

    • greater number of trinucleotide repeats may be unstable, & progressive amplification of repeat number can be seen in successive generations

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  5. What’s an example of a disease that exhibits Anticipation?
    Myotonic Dystrophy

    • affects skeletal & smooth muscle as well as the eye, heart, endocrine system, & CNS

    • Myotonia = sustained muscle contractions

    • is an Autosomal Dominant disease showing anticipation

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  6. What are the 3 phenotypes of Myotonic Dystrophy?
    1. Mild: cataracts, mild myotonia, normal life span

    2. Classic: muscle weakness, wasting, myotonia, cataract, possibly shortened life span

    3. Congenital: severe hypotonia at birth, often with respiratory insufficiency & early death; intellectual disability is common; *congenital form occurs from maternal transmission only
  7. How can you differentiate between mild, classic, & congenital forms of Myotonic Dystrophy?
    by the number of repeats
  8. Premutation
    when the trinucleotide repeat size isn’t long enough to result in symptoms, but the person with the premutation is at risk of having a child who may exhibit symptoms
  9. What is the most common inherited cause of intellectual disability?
    Fragile X Syndrome
  10. Fragile X Syndrome
    • subtle facial feature: long face, large ears

    • caused by CGG repeat expansion in FMR1 gene on X chromosome (a fragile site)

    • also an example of a disease that exhibits anticipation

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  11. When does expansion from premutation to full CGG repeat mutation occur in Fragile X Syndrome?
    ONLY through FEMALE meiosis

    • the meiosis of a daughter of a healthy male who carries a premutation is UNSTABLE

    • trinucleotide expansion won’t occur during his meiosis but when his daughter (who has a healthy carrier male father) has an offspring, expansion can happen

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  12. Fragile X Syndrome Repeat Numbers
    • 45 repeats: normal; no associated phenotype

    • 45 - 54: intermediate; no associated phenotype [child of this person is at risk for a premutation though]

    • 55 - 200: premutation; at risk for Fragile X-associated Tremor/Ataxia Syndrome (FXTAS)

    • > 200: FULL mutation; all males are intellectually disabled, 50% of females will have an ID & 50% will be normal

    - it doesn’t matter if you have 205 or 2,000 repeats; gene is turned off in both situations (disease severity doesn’t depend on # of repeats)
  13. FMR1 Gene Methylation Status in Fragile X
    • • when someone has a Full Mutation (>200 CGG repeats) their FMR1 gene is completely methylated
    • - this means the gene is turned off & nonfunctional

    • all other mutation forms (normal, intermediate, pre), the FMR1 gene is unmethylated, meaning the gene is turned on & working
  14. Fragile X Premutation Carriers (Expanded)
    • females have increased risk of Premature Ovarian Insufficiency (POI), menopause before age 40

    • • males are at risk for FXTAS, a late-onset condition with progressive intention tremor, ataxia, cognitive decline, generalized brain atrophy
    • - don’t screen for this because you might pick up on adult onset symptoms that people don’t want to be aware of

    • doesn’t affect intelligence, IQ tends to be normal
  15. Mosaicism
    presence of more than one cell line in an individual
  16. Explain the idea that all women are mosaics:
    some cells have one X active, other cells have the other X active (because of Lyonization)
  17. Somatic Mosaicism
    usually caused by a post-zygotic mutation which affects a certain percentage of cells in an individual

    • disease severity is variable because it depends on proportion of mutated cells in each tissue
  18. What are 2 examples of diseases caused by Somatic Mosaicism?
    1. Mosaic Down Syndrome

    2. Pallister-Killian Syndrome (ALWAYS MOSAIC, would be lethal otherwise)
  19. Mosaic Down Syndrome
    • accounts for 1-2% of DS cases

    • may be less severe than individuals with full trisomy 21

    • features depend on proportion of cells with trisomy 21 in each tissue type

    • severity is impossible to predict
  20. Pallister-Killian Syndrome
    • • caused by mosaic tetrasomy 12p
    • - 4 copies of the short arm of chromosome 12

    • characterized by low muscle tone, characteristic facies, high arched palate, hypopigmentation, extra nipples, developmental delays, diaphragmatic hernias
  21. Gonadal Mosaicism
    presence of more than one cell line in the gonadal cells but not in the rest of the body

    • person with the GM is unaffected by the condition

    • the mutation occurred in precursor egg or sperm cell

    • is important for recurrrence risk assessment for apparently de novo dominant disorders
  22. When is Gonadal Mosaicism inferred?
    • when at least 2 offspring have an AD disorder with no other family history

    - eg. if children with an “apparently” new mutation had unaffected parents & a negative family history
  23. Genomic Imprinting
    • the different epigenetic modifications of maternal & paternal genetic contributions to the zygote

    - eg. silencing (via methylation) of maternal or paternal genes in the zygote

    • some genes are expressed preferentially in either the maternal or paternal genotype
  24. What are 3 mechanisms of Genomic Imprinting?
    • 1. Uniparental Disomy
    • 2. Heterozygous Deletion
    • 3. Mutation
  25. Digynic Triploidy
    • 2 sets of maternal chromosomes, one set of paternal chromosomes

    • very small fetus & placenta
  26. Diandric Triploidy
    • 2 sets of paternal chromosomes, one set of maternal chromosomes

    • normal to slightly small fetus with large cystic placenta

    * SAB triploidy pregnancies tell us there’s something different about maternal & paternal chromosomes → serves as evidence of imprinting*
  27. Uniparental Disomy (UPD)
    the presence of 2 homologous chromosomes inherited from only 1 parent

    • this means 1 parent has contributed 2 copies of a chromosome & the other parent has contributed no copies

    • may play a role in unexplained pregnancy loss & IUGR (intrauterine growth restriction)

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  28. Heterodisomy
    non-disjunction in meiosis I occurs, resulting in a parent passing on 1 copy of each homolog

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    (meiosis I → hetero)
  29. Isodisomy
    non-disjunction in meiosis II occurs, resulting in a parent passing on 2 copies of the same chromosome

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    • (meiosis II → iso)
  30. 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
  31. When is UPD clinically significant?
    when it involves chromosomes with imprinted genes or chromosomes containing an autosomal recessive (eg. CF) mutation (isodisomy)
  32. Trisomic Conception
    if an oocyte or spermatocyte that has 2 copies of a chromosome is joined by sperm or oocyte with 1 chromosome in question, there are 3 copies of the chromosome, & the copy of the chromosome most likely to be lost is from the parent who only gave ONE
  33. 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
  34. 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
  35. Russell Silver Syndrome
    • • growth disorder with prenatal onset
    • • characterized by small, triangular face with distinctive facial features
    • • ~10% of cases are caused by maternal UPD of chromosome 7
  36. Prader-Willi Syndrome
    • • caused by
    • 1. Paternal gene deletion on chromosome 15 (Prader → P for Paternal)

    2. Maternal UPD of chromosome 15

    • hypotonia, intellectual disability, hyperphagia, obesity :(

    • in a normal individual, the corresponding maternal gene is imprinted & the paternal gene is expressed

    • with no functional paternal copy of the gene there is no expression → disorder
  37. Angelman Syndrome
    • • caused by:
    • 1. Maternal gene deletion on chromosome 15 (Angel = feminine)

    2. Paternal UPD of chromosome 15

    • severe intellectual disability, movement disorder, seizures

    • in a normal individual, the corresponding paternal gene is imprinted & the maternal gene is expressed

    • caused by a lack of expression from genes in the critical region that are normally only expressed from the maternal allele
Card Set
3 NonMendelian Genetics
Genetics Exam 1