Inversions
Epidemiology and
Etiology:
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Estimates of frequency:
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Pericentric – 0.12 to 0.7%
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Paracentric – 0.1 to 0.5%
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May be the most common form of chromosomal polymorphism found in
nature
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Many small inversions may remain undetected
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Most are inherited (85-90%)
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Mechanisms of formation:
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NAHR:
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Recombination between inverted homologous sequences on the same
chromosome
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Terminology:
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Simple inversion
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2-break event involving just one chromosome
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Complex inversion
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Coexists with another rearrangement in the same chromosome
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Pericentric inversion
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Inverted segment includes centromere
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Paracentric inversion
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Inverted segment does not include centromere
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Nomenclature:
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Ex. 46,XX,inv(3)(p25q21)
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Inversions with breakpoints within the heterochromatic regions of
chromosomes 1, 9, 16, and Y are frequently seen
·
Regarded as variants, not abnormal
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Other apparently benign recurring pericentric
inversions with breakpoints very near the centromere:
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2, 3, 10, and Y
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Preferential sites of pericentric
inversions:
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Inv(2)(p11.2q13) is most common inversion not involving centromeric heterochromatin
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2p13, 2q21
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5p13, 5q31
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6q21
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10q22
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12q13
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Other recurrent pericentric inversions:
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inv(3)(p25q21)
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inv(4)(p14q35)
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inv(10)(p11q25)
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inv(13)(p13q21)
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inv(21)(p12q21.1)
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Preferential sites of paracentric
inversions:
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Factor VIII gene
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Hemophilia A can be caused by recombination between inverted
homologous sequences
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Genesis of imbalanced gametes:
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One (or an uneven number of) crossover(s) within the inversion
loop (resulting in homosynapsis), between a chromatid of the normal homolog and a chromatid
of the inversion chromosome leads to the production of two complementary
recombinant chromosomes:
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One with a duplication of the distal segment of the short arm and
a deletion of the distal segment of the long arm
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One with a deletion of the distal segment of the short arm and a
duplication of the distal segment of the long arm
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Typically only one of these (the least monosomic)
is viable if any
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Small inversions may not be able to form an inversion loop and
instead will “balloon out” (asynapsis) or lie
adjacent but unmatched (heterosynapsis), and
recombination cannot occur in this situation
·
If both breakpoints are in G-light regions, homosynapsis
is more likely than if one or both breakpoints are in a G-dark band
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Sperm studies show that longer inversions are more likely to form
recombinants (13-38%) while short inversions do not form recombinants
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However, some inversions seem to suppress recombinants (ex.
inv(1)(p31q12)
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Common sites:
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Gross features:
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Histologic
features:
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Immunophenotype:
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Marker: |
Sensitivity: |
Specificity: |
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Molecular features:
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Other features:
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In most cases does not perturb the smooth running of the genome
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Xq breakpoint
within the critical regions can cause gonadal
insufficiency
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Rarely breakpoint occurs within a gene and is directly pathogenic
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De novo inversion in a fetus/child:
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9.4% overall risk of serious congenital anomaly (amniotic fluid)
(Warburton 1991)
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Submicroscopic deletion may be generated during the formation of
a paracentric inversion (risk is close to negligible)
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However, Angelman/Prader-Wili
region should be checked for breakpoints near this region in proximal 15q
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Mosaic inversions:
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Parent:
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Rare
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References:
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Gardner RJM, Sutherland GR. Chromosome abnormalities and genetic
counseling. Oxford University Press; 2004.
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Warburton D. De novo balanced chromosome rearrangements and extra
marker chromosomes identified at prenatal diagnosis: clinical significance and
distribution of breakpoints. Am J Hum Genet. 1991;49(5):995-1013.