ABMG Board Review Clinical Cytogenetics

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ABMG Board Review Clinical Cytogenetics

• Meiosis/Mitosis
• Chromosome abnormalities Numerical Struct
  ural Nomenclature Segregation
• Nomenclature
• Prenatal cytogenetics
• Chromosome instability syndromes

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ABMG Board Review Clinical Cytogenetics (not
covered)

• Sex chromosome abnormalities
• X-inactivation
• Cancer cytogenetics
• Fragile X
• Deletion/Duplication syndromes
• Uniparental disomy / Genomic imprinting

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Nondisjunction leads to imbalance of genetic
material in gametes

• MEIOSIS I
• MEIOSIS II

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Chromosome Origin of Extra
Abnormality Chromosome
Paternal Maternal _____________________
_____________________ trisomy 2 2
2 10 0 4 13 2 5 14
2 6 15 3 8 16 0
58 18 2 34 21 14 213 22 0
11 XXY 58 75 XXX 3
44 __________________________________________
Terry Hassold (unpublished) data from both
spontaneous abortions and live births.
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Meiotic Error in 200 Families with Trisomy
21 Maternal origin 188meiosis I error (M1)
128 MI/MIM277.1 meiosis II error (M2)
038 M2/MIM222.9 meiosis error
unknown 022 Paternal origin 009 meiosis I error
(PI) 002 PI/PIP222.2 meiosis II error (P2)
007 P2/PIP277.8 meiosis error
unknown 000 Origin unknown 003 _______________
___________________________ Stelianos
Antonarakis (unpublished) data from DNA
polymorphisms
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AUTOSOMAL ANEUPLOIDIES

• Trisomy 21 95 all Down Syndrome 5
  Robertsonian mosaicism 1/700 births, 1.21
  male female
• Trisomy 18 1/6000-8000 births 13-4 male
  female
• Trisomy 13 1/12000 births
• Trisomy 8 Rare, most mosaic 2-31 male
  female
• Trisomy 9 Rare, most mosaic
• Trisomy 16 Most frequent autosomal trisomy in
  spontaneous abortuses
• Trisomy 20 Frequently detected prenatally,
  rarely seen in liveborns. All mosaic, most
  confined to extra-embryonic tissues.
• Trisomy 22 Rare, most cases are not mosaic.

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PARTIAL AUTOSOMAL ANEUPLOIDIES

• Tetrasomy 5p 8p all mosaic 9p
  12p Pallister Killian (all mosaic) 18p
• Supernumerary marker inv dup(15) 40 all
  marker chromosomes dup 22q11.2 Cat-eye syndrome

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TRANSLOCATIONS

• Robertsonian
• Reciprocal

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45,XX,der(1314)(q10q10)
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46,XY,13,der(1314)(q10q10)mat
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46,XX,t(1122)(q23q11.2)

• First (perhaps only) recurring constitutional
  reciprocal translocation
• More than 100 apparently unrelated families
• Breakpoints cluster in AT rich palindromic
  sequences
• Carriers are phenotypically normal
• 2-10 risk of liveborn child with unbalanced
  karyotype

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47,XX,der(22)t(1122)(q23q11.2)
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Chromosome nomenclature
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Chromosome Nomenclature

• Constitutional Aneuploidy of Sex
  Chromosomes 45,X 47,XXY
• Acquired Aneuploidy of Sex Chromosomes 45,X,-X
  47,XY,X
• Numerical Abnormalities of Autosomes 47,XY,18
  45,XY,-21
• Mosaics mos 45,X4/46,XX16
• Deletions 46,XY,del(1)(q32) 46,XY,del(1)(q2
  1q32)
• Structural Abnormalities 46,XY,t(36)(p21q23
  ) 46,XY,der(3)t(36)(p21q23) 45,XY,der(3)t
  (36)(p21q23),-6 47,XY,der(3)t(36)(p21q23)

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Meiotic pairing configuration for balanced
chromosome translocation

• Alternate normal balanced
• Adjacent 1 and 2 partial monosomy partial
  trisomy
• 31 Segregation partial monosomy partial
  trisomy trisomy monosomy
• 40 Segregation

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Chromosome segregation

• Structural abnormality of father
  46,XY,t(36)(p21q23)
• Structural abnormalities of offspring 46,XY,t(3
  6)(p21q23)pat 46,XY,der(3)t(36)(p21q23)pat
  45,XY,der(3)t(36)(p21q23)pat,-6 47,XY,der(3)
  t(36)(p21q23)pat

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Chromosome segregation

• Structural abnormalities of offspring 46,XY,t(3
  6)(p21q23)pat alternate 46,XY,der(3)t(36)
  (p21q23)pat 45,XY,der(3)t(36)(p21q23)pat,-6
  47,XY,der(3)t(36)(p21q23)pat

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Chromosome segregation

• Structural abnormalities of offspring 46,XY,t(3
  6)(p21q23)pat 46,XY,der(3)t(36)(p21q23)pat
  adjacent 1 45,XY,der(3)t(36)(p21q23)pat,-6
  47,XY,der(3)t(36)(p21q23)pat

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Chromosome segregation

• Structural abnormalities of offspring 46,XY,t(3
  6)(p21q23)pat 46,XY,der(3)t(36)(p21q23)pat
  45,XY,der(3)t(36)(p21q23)pat,-6 31
  segregation 47,XY,der(3)t(36)(p21q23)pat

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Chromosome segregation

• Structural abnormalities of offspring 46,XY,t(3
  6)(p21q23)pat 46,XY,der(3)t(36)(p21q23)pat
  45,XY,der(3)t(36)(p21q23)pat,-6 47,XY,der(3)
  t(36)(p21q23)pat 31 segregation

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Frequency of Chromosome Abnormalities in
Unselected Spontaneous AbortionsAdapted from The
Principles of Cytogenetics, Second addition Ch.
12 Prenatal Cytogenetics
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Chromosome instability syndromes

• Fanconi anemia
• Ataxia telangiectasia
• Bloom Syndrome
• Nijmegen breakage syndrome
• ICF syndrome
• Robert syndrome
• Werner syndrome

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Chromosome instability syndromes

• All autosomal recessive
• Show increased frequency of chromosome changes
  (spontaneous and induced)
• Associated with increased risk of developing
  malignancies (except Roberts)
• Disorders of DNA recombination (DNA repair, cell
  cycle control, apoptosis)

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Fanconi anemia

• Spontaneous chromosome breakage in vitro and in
  vivo
• Chromatid gaps and breaks, fragments, rings and
  multiradial formations
• Considerable clinical and molecular
  heterogeneity. DEB and MMC used to enhance
  breakage and diagnosis.

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Ataxia telangiectasia

• High sensitivity to ionizing radiation
• Increased frequency of chromosomes 7 and 14
  rearrangements (Ig and TCR genes)

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Bloom syndrome10-fold elevated level of sister
chromatid exchange
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Recommended reading.
The Principles of Clinical Cytogenetics, second
edition. 2005. Gersen SL and Keagle MB, eds.
Chromosome Abnormalities and Genetic
Counseling, second edition. 1996. Gardner RJM and
Sutherland GR. Human Chromosomes, fourth
edition. 2000. Miller OJ and Therman E.