Robertsonian Translocations

Epidemiology and Etiology:

• de novo Robertsonian translocations:
• de novo Robertsonian translocations are predominantly maternal origin
• occur predominantly during oogenesis (maternal meiosis)
• no parental bias for homologous Robertsonians in contrast
• de novo translocation Down syndrome most likely reflects translocation of one 21 chromatid to a 14 chromatid at maternal meiosis
• de novo homologous Robertsonian translocations are most likely formed after conception in one of the very first mitoses
• resulting heterozygous arms
• some are homozygous, forming in meiosis II or very early postzygotic stage
• 1:1000 newborns
• rob(13q14q) is most common (74%)
• this is the most common single rearrangement in humans
• rob(14q21q) is next common (8%)
• homologous inverted segments in these two pairs of chromosomes may be responsible for their increased frequency
• others are < 5%
• homologous Robertsonians are rare in contrast to nonhomologous Robertsonians
• Non-homologous:
• Involving two different chromosomes
• Can be passed on through many generations
• Homologous (very rare)
• Involving two homologous chromosomes
• De novo (almost always)
• Most nonhomologous Robertsonians are in fact dicentric (but stable due to their close proximity)
• Most homologous Robertsonians are monocentric (more properly isochromosomes)
• 90% may be composed on identical rather than unique homologuos arms
• Mechanisms:
• Non-allelic homologous recombination (NAHR):
• Homologous recombination between shared sequences on the short arms of the acrocentric chromosomes
• Satellite III DNA sequences
• Other adjacent repetitive sequences within the short arms of acrocentric chromosomes (ex. NORs)
• 18s and 28s rRNA genes
• Postulated to be in opposite orientations in chr 14 in comparison to chr 13 and chr 21
• Close association of NORs within the nucleus could promote the formation of Robertsonian translocations
• Centric fusion:
• Monocentric product
• Union following breakage in one short arm and one long arm
• Monocentric product
• Union following breakage of both short arms
• Dicentric product
• rob(13q14q) and rob(14q21q) are always dicentric
• one centromere is “suppressed” and the product appears monocentric
• common ROBs may have a different mechanism than rare ROBs
• nucleolar organizer regions (NORs) are lost in the derivative chromosome
• Behaviour of Robertsonian translocaitons during meiosis:
• Heterozygote:
• Trivalent synapse
• Alternate segregation is favoured
• One cell with one normal of each chromosome
• One cell with the derivative chromosome (balanced)
• Exception to this is a female carrier of a Robertsonian translocation involving 21
• Risk of translocation Down syndrome is substantial (~15% at amniocentesis)
• “back-mutational fission” can revert a Robertsonian translocation to 2 separate chromosomes (very rare)
• “Correction” of translocation trisomy may result in uniparental disomy
• Rare in rob(13q14q)

Common sites:

Gross features:

Histologic features:

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Molecular features:

Other features:

• Parent with a balanced Robertsonian:
• Those involving 21 convey a risk of Down syndrome
• Risk of UPD (< 1%)
• Homologous Robertsonian translocations:
• conceptus will be trisomic or monosomic
• post-zygotic “correction” is highly unlikely, and would lead to UPD
• rob(21q21q) is extremely rare but famous due to near 100% chance of having a translocation trisomy 21 conceptus
• translocation trisomy 13 or 21 can be viable
• Infertility
• Robertsonian heterozygotes are 7x more likely in infertile couples
• Likely due to unbalanced conceptuses spontaneously aborting
• Robertsonian heterozygotsity is 10x more likely in an oligospermic male
• May be due to interference of unpaired heterochromatic regions of the short arms interfering with pairing in the X-Y bivalent and blocking spermatogenesis
• May be due to loss of a spermatogenesis allele in proximal 14q
• rob(13q14)
• Small risk of translocation trisomy 13 in conceptus (< 0.4% in one study)
• 0.6% risk of UPD
• Is prenatal testing for UPD justified given the small risk?
• rob(14q21q)
• cause of most familial translocation trisomy 21 (more frequent translocation than the others)
• female heterozygote has a risk of 15% (10% liveborn)
• male heterozygote has a risk of 0.5%
• 0.6% risk of UPD
• rob(13q15q)
• few data available
• thought to be similar risks as for ro(13q14)
• 0.5% or less for tranlocation trisomy 13
• 0.6% risk for UPD15
• rob(13q21q)
• risk for translocation Down syndrome at amniocentesis is same as for rob(14q21q):
• ~15% for female
• 0.5% or less for male
• Risk for translocation trisomy 13 is 0.5% or less
• rob(13q22q)
• risk for trisomy 13 presumed to be similar to that for rob(13q14q)
• 0.5% or less
• rob(14q15q)
• theoretical risk of UPD 14 or 15 (0.6%?)
• only one case on record (maternal)
• rob(14q22q) and rob(15q22q)
• theoretical risk of UPD (0.6%?)
• rob(15q21q)
• little data available
• risk of translocation trisomy 21 likely same as for rob(14q21q)
• 15% for female
• 0.5% for male
• Risk of UPD (0.6%?)
• rob(21q22q)
• similar risk of translocation trisomy 21 as rob(14q21q)
• 15% for female
• 0.5% for male
• Fetus / child with a balanced Robertsonian:
• De novo:
• 3.7% overall risk of serious congenital anomaly (amniotic fluid) (Warburton 1991)
• 66% risk for UPD for de novo homologous Robertsonian or isochromosome involving 14 or 15
• Paternal in all cases, resulting from paternal isochromosome formation
• Those involving 14 and 15 convey a risk of imbalance due to uniparental disomy
• 0.6% for non-homologous Robertsonaian involving 14 or 15
• UPD 15(mat)
• Prader-Willi syndrome
• UPD 15(pat)
• Angelman syndrome
• UPD 14(mat)
• Variable phenotype (may be mild)
• Growth retardation
1. Relative macrocephaly
• Mild developmental delay
• Mildly dysmorphic facies
• UPD 14(pat)
• 2 recorded cases
• Severe intellectual defect
• dysmorphism

References:

· Gardner RJM, Sutherland GR. Chromosome Abnormalities and Genetic Counseling. 2nd ed. Oxford University Press, USA; 1996.

· Shaffer LG, Agan N, Goldberg JD, et al. American College of Medical Genetics statement of diagnostic testing for uniparental disomy. Genet. Med. 3(3):206-11.

· 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.

· CCMG Guidelines: Prenatal and Postnatal Diagnostic Testing for Uniparental Disomy (UPD). Clinical Genetics (in press, 2010).