Ring Chromosomes

r(6)

r(13)

r(18)

r(20)

r(21)

r(X)

Epidemiology and Etiology:

• Rare
• 1:27,000 to 1:60,000 of consecutive newborn and prenatal diagnosis studies
• De novo usually
• No more than 1% are inherited
• 13 and 18 are most commonly involved
• May contain more than one chromosome
• If ring chromosome replaces normal homolog
• Partial monosomy for both long and short arm material (often)
• Phenotype depends on amount and nature of the deleted material
• If ring chromosome is supernumerary
• Partial trisomies result
• Phenotype depends on amount and nature of the trisomic material as well as degree of mosaicism
• Mechanisms:
• Breakage of both arms of a chromosome with subsequent fusion of the ends
• Loss of distal segments
• Transverse misdivision of the centromere combined with a U-type exchange on one of the chromosome arms
• Resulting loss of centromeric satellite DNA
• Telomere fusion
• No loss of genetic material detected
• Acentric ring:
• Fusion of the ends of a chromosome fragment with no centromere
• A neocentromere forms
• Instability (“dynamic mosaicism”)
• Thought to result from sister chromatid exchanges that occur in the rign chromosome before cell division
• Result in the formation of double sized dicentric rings and interlocking rings
• During mitosis these can break if centromeres go to opposite poles
• Subsequent further ring formation
• Entire ring can be lost alternatively
• Smaller rings are more stable than larger rings

Common sites:

Gross features:

Histologic features:

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Molecular features:

Other features:

• Nomenclature:
• Ex. 46,XX,r(7)(p22q36)
• Clinical Features:
• “ring syndrome”
• The larger the chromosome involved, the more severe the phenotype
• Likely due to above “dynamic mosaicism” leading to growth restriction from non-viable cells
• Severe growth retardation
• No major malformations
• Minor anomalies often
• Mild to moderate mental retardation often
• Milder for smaller chromosomes
• Not seen in r(21) or r(22)
• Partial monosomy often results in major dysmorphogenesis and mental retardation
• Even if the deletion is not visible on G-banding
• But telomere-telomere fusions have no partial monosomy
• Although infertility is not a feature, phenotype is usually severe enough that kids are no question
• Risk of UPD
• Due to loss of ring and subsequent “monosomy rescue”
• Often mosaic
• Risk of passing on to kids is low
• Most do not have kids for social reasons
• ~40% of children of a ring carrier are also ring carriers
• 90% of transmitted cases from mother
• Suggests that males with rings are infertile
• 11, 14, 15, 17, 18, 20, 21, and 22 have been reported
• If it is passed on, half have a similar phenotype
• A third have a more severe phenotype
• Almost all instances of parent-to-child transmission involve the mother as the carrier
• mosaics may or may not be of normal intellect

References:

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

· Gersen SL, Keagle MB. The Principles of Clinical Cytogenetics. 2nd ed. Humana Press; 2004.