Aneuploidy
Epidemiology and
Etiology:
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~2% of human sperm by FISH
·
20-25% of oocytes
·
Estimated at least 5% of clinically recognized pregnancies
·
Estimated 10-30% of fertilized human eggs
·
~20% of IVF embryos
·
35% of spontaneous abortions (6 to 20 wk)
·
Trisomies for nearly all
chromosomes
·
Turner most common (10% of SA)
·
Trisomies 16, 21, and 22
(50% of all trisomies in SA)
·
~4% of stillbirths (> 20 wk)
·
0.3% of liveborns
·
Trisomy 21 most common
·
Sex chromosome trisomies next
·
Most perish in utero
·
Leading genetic cause of pregnancy loss
·
1/3 of miscarriages
·
Most common cause of mental retardation
·
Errors in meiotic segregation
·
Cis
(chromosome-specific) effects influence the patterns
·
Most frequent in females
·
Especially during meiosis I
·
~90-95% of most trisomies
·
Almost always for trisomy 16
·
Advancing maternal age is a major risk factor
·
Little is known about the reason for this effect
·
“limited oocyte pool” model
·
Relative scarcity of oocytes at optimal
stages of maturation
·
MI errors:
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Maternal MI errors predominate almost all trisomies
·
Most if not all of trisomy 16
·
2/3 of sex chromosome trisomies
·
‘true’ nondisjunction
·
Failure to resolve chiasmata between
homologous chromosomes at anaphase I
·
Both homologues segregate together
·
‘achiasmate’ nondisjunction
·
Premature resolution of chiasmata or
the failure to establish chiasmata between a pair of
homologues
·
Independent segregation of homologues that happen to both
segregate into the same pole of the MI spindle
·
Premature segregation of sister chromatids
(PSSC)
·
Can result in segregation of a whole chromosome and a sister chromatid to one pole at MI
·
MII errors:
·
Most cases of trisomy 18
·
Nondisjunction:
·
Failure of sister chromatid separation
·
Others
·
Disturbances of recombination process invariably lead to meiotic
arrest or gross abnormalities in chromosome segregation or at least increased
levels of non-disjunction
·
Significant reductions in recombination events are a feature of
all MI-derived trisomies so far studied
·
Location of recombinational events (exchanges)
is important:
·
Exchanges can be either too near or too far from the centromere, imparting a risk for non-disjunction
·
Has been demonstrated for trisomy 21
and trisomy 16
·
Presence of a pericentromeric exchange
might increase the likelihood of PSSC at MI
·
Other suggested risk factors (none proven):
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Parental irradiation
·
Oral contraceptives
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Fertility drugs
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Thyroid antibodies
·
Alcohol
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Seasonality
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Parity
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Maternal diabetes
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Consanguinity
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Allelic combinations at specific loci
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Presence of certain types of chromosome polymorphisms
Common sites:
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Gross features:
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Histologic
features:
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Immunophenotype:
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Molecular features:
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Other features:
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References:
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Hassold T, Hunt P. To
err (meiotically) is human: the genesis of human aneuploidy. Nat. Rev. Genet. 2001;2(4):280-291.