Abnormalities in chromosome structure, their causes and clinical presentation in man

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Definitions[edit | edit source]

  1. Balanced aberrations – phenotypically harmless; no loss and no gain of unique genetic material
    • translocation
    • inversion
    • insertion
  2. Unbalanced aberrations – usually phenotypically harmful; with loss or gain of genetic material
    • deletion
    • duplication
    • isochromosome
    • ring chromosome

Origin of structural aberrations[edit | edit source]

chromosome breaks – on one or more chromosomes, in one or more breakpoints

  • stable products (with centromere and two telomeres) – regular segregation in mitotic cycles, rearrangement present in all cells of organism
  • unstable products – irregular segregation in mitotic cycles
    • acentric fragments - usually lost at anaphase
    • dicentric fragments - dragged to both poles of spindle, randomly broken or lost in some cells (resulting in secondary rearrangement formation, mosaicism or monosomy)

Translocation[edit | edit source]

Exchange or transfer of chromosomal segments from one chromosome to another. Change in gene localization, but no gain or loss of DNA → balanced rearrangement.


  • reciprocal translocations – breakage and exchange of chromosomal material between at least two nonhomologous chromosomes – may result in changes in size and arm ratio; no phenotype effect for carriers except semisterility (altered gametes with imbalanced chromosome complement may be formed due to unbalanced segregation of the involved chromosomes)
  • Robertsonian translocations – breakage of two acrocentric chromosomes (13, 14, 15, 21 or 22) and their subsequent centric fusion of the long arms of two acrocentric chromosomes – results in change of total chromosome number (46 → 45);

short arms are lost without clinical importance as containing genes for rRNA (multiple copies on the other acrocentric chromosomes); no phenotype effect for carriers except semisterility; risk for having a baby with Down syndrome if chromosome 21 is involved in translocation segregation of trivalent structure in Robertsonian translocations (see Figure No. 1)

Inversion[edit | edit source]

180° change of direction of a chromosomal segment (two breaks on one chromosome, rotation of the middle segment and rejoining) Change in gene order, but no gain or loss of DNA → balanced rearrangement Normal phenotype except position effect variegation

  • break within a gene may disrupt gene function
  • breaks within 2 genes may cause gene fusion

(more details in question No. 114 – Chromosomal aberrations in cancer cells)

Inversion loop formed at meiosis I – crossover within the loop may cause chromosome recombination and imbalanced gametes formation with reduced total number of viable gametes. Risk for offspring – fetal abnormalities or reduced fertility (recurrent miscarriages).


  • pericentric inversion – inversion spans centromere, can be detected microscopically by altered arm ratio and change in bands order
  • paracentric inversion – centromere outside inversion, no change of arm ratio, can be detected only by change in bands order

Deletion[edit | edit source]

Loss of segment of DNA → unbalanced rearrangement. Origin: breakage and loss of acentric segment, unequal crossover, ring chromosome,...


  • terminal – one break on one chromosome, distal acentric segment lost
  • interstitial – two breaks on one chromosome arm, middle segment lost, the segments left rejoined

Microdeletion syndromes (contiguous genes syndromes)[edit | edit source]

  • variable phenotype (mental retardation, congenital anomalies, craniofacial dysmorphy, growth retardation)
  • mostly submicroscopic deletion < 4 Mb
  • loss of gene block, variable phenotype consequences depending on size of deleted segment and genes involved
  • Clinical presentations:
    • Phenotypic effects depend on particular genetic content (locus and size of lost and/or amplified genomic segment) involved in rearrangement.

Clinically important syndromes with structural aberrations in man[edit | edit source]

  1. Down syndrome – translocation form, 4-5% of all Down sy cases in population – unbalanced Robertsonian translocation; karyotype e.g. 46,XY,rob(14;21),+21
    • one of parents could be balanced carrier of Robertsonian translocation with karyotype e.g. 45,XY,rob(14;21)
    • the recurrence risk of having Down sy baby in balanced carriers is theoretically 1/3, in practice is lower (male carriers: 1-3%, female carriers: 5-10%), except transl. 21;21
    • in case of translocation 21;21 is risk of recurrence 100% for any balanced carrier parent
    • Symptoms of Down syndrome (see question No. 38 – Autosomal aneuploidy in man)
  2. Turner syndrome – deletion form, deletion on the short arm of chromosome X; karyotype 46,X,del(Xp)
    • symptoms very similar to monosomy X variant of Turner syndrome but modified by amount of deleted genes; critical deleted region is pseudoautosomal region 1 (PAR1) on Xp, incl. gene SHOX (causing short stature and dysproportions in extremities lenght)
    • phenotype is usually variable and milder, in some cases fertility could be preserved
    • Symptoms of Turner syndrome (see question No. 39 – Gonosomal aneuploidy in man)
  3. Cri du chat (cat cry syndrome) – terminal deletion on the short arm of chromosome 5
    • Phenotype:
      • microcephaly, severe somatic and mental retardation, round „moon-shaped“ face, hypoplastic larynx in early months of childhood – high shrill cry (like a mewing cat)
  4. Prader-Willi sy – interstitial microdeletion on the short arm of paternal chromosome 15
    • Etiology: microdeletion is detected approx. in 70% of children with Prader-Willi sy, others are caused by uniparental (maternal) disomy with genomic imprinting effect, rarely by point mutations of genes in critical region for Prader-Willi/Angelman syndromes or imprinting regulating genes
    • Phenotype:
      • Newborn, early infants - severe hypotonia, developmental delay
      • Later – mild to moderate mental retardation, overeating – extreme obesity with possible letal complications (diabetes mellitus, cardiovascular disorders,…), hypogenitalism, behavioral disorders (sleeplessness, anger, annoyance,...)
  5. Angelman sy – interstitial microdeletion on the short arm of maternal chromosome 15
    • Etiology: microdeletion is detected approx. in 70% of children with Angelman sy, others are caused by uniparental (paternal) disomy with genomic imprinting effect or point mutations of genes in critical region for Prader-Willi/Angelman syndromes
    • Phenotype:
      • severe mental retardation, absent speech, jerky movements, ataxia, stiff-legged gait, epileptic seizures, behavioral disorders (stereotypic movements, paroxysms of easily provoked laughter), „happy puppet“ syndrome
      • Genomic imprinting mechanisms (see question No. 52 – Epigenetics, genetic imprinting)
  6. Other microdeletion syndromes:
    • DiGeorge/VCFS/CATCH 22 sy (deletion on chromosome 22)
    • Wolf-Hirschhorn sy (deletion on chromosome 4)
    • Williams-Beuren sy (deletion on chromosome 7)