Marker Chromosomes

Extra Structurally Abnormal Chromosomes (ESACs)

Supernumerary Marker Chromosomes (SMCs)

B Chromosomes

Inv dup(15)

Supernumary bisatellited dicentric marker derived from chr 22

Der(22)t(11;22)(q23;q11)

Isochromosome 12p

Isochromosome 18p

Isochromosome 9p

Epidemiology and Etiology:

· “Small supernumerary chromosomes that generally lack a distinct banding pattern”

· “structurally abnormal chromosomes that cannot be identified or characterized unambiguously by conventional banding cytogenetics alone”

o “generally equal in size or smaller than a chromosome 20 of the same metaphase spread”

· 0.1% of prenatal karyotypes

· 0.07% in newborns

o 0.24/1000 liveborns (1 in 2500 live births)

o 3/1000 in mentally retarded population

o 0.288% in mentally retarded

o 0.044% in consecutively studied postnatal cases

· 0.125% in infertility studies

· Incidence may increase with maternal age (Hastings et al, 1999)

o Predominantly transmitted maternally

· 40% are familial

· Frequently in mosaic form

o 54% in a large series of 150 SMCs

· 80% of supernumerary marker chromosomes (SMCs) are derived from the short arm and pericentromeric regions of acrocentric chromosomes

· 50% of SMCs include the short arm of chr 15

o 40% of SMCs are idic(15)

o distamycin/DAPI (DA/DAPI) positive

o 70% of these are described as inv dup (15)

· Sex chromosome-derived:

o Most of the time an abnormal chromosome replaces one of the sex chromosomes

o 73% der(Y)

· Most are isodicentric

· Some are ring

o 27% der(X)

· Most are ring

· Some are min

· Classes of marker chromosomes proposed

Molecular features:

• FISH is very useful in evaluation
• WCP probes
• Not informative for markers smaller than 17p in general
• Centromeric probes
• Multicolour banding (MCB)
• Useful for smaller markers (down to half size of 17p)
• cenM-FISH
• CM-FISH
• M-FISH

Other features:

• Phenotype:
• If de novo, serious counselling problem
• Phenotypic consequences of other markers other than idic(15) and idic(22) are not well defined
• Lack of good outcome correlation
• Presence or absence of euchromatin on G-banding is important
• Those containing euchromatin are generally not benign
• Ex. dicentric bisatellited markers containing variable amounts of long-arm material
• 10-30% risk of abnormal phenotype
• 7% for sSMCs of 13, 14, 21, 22
• 28% for sSMCs of non-acrocentric autosomes
• <2% for small bisatellited monocentromeric ESAC
• Average estimate of risk of abnormality in immediate newborn period:
• 15% for nonsatellited ESAC
• 70% of SMCs derived from non-acrocentric chromosomes are not associated with clinical symptoms
• 11% for satellited ESAC
• See table in Gardner, p. 370 for approximate risks for individual ESACs
• Some are harmless
• Markers containing only heterochromatin or short arms of acrocentric chromosomes have no phenotypic consequences
• Phenotype depends on the chromosomal material present
• Usually trisomy or tetrasomy of pericentric material
• No clear “symptomatic” or “non-symptomatic” regions as yet
• Der(X) markers:
• Presence of XIST gene is important
• Lack of follow-up for sexual development effects
• Der(Y) chromosomes:
• Small der(Y) – <5% risk of abnormal phenotype
• Unlikely to cause phenotypic effect in a male
• In a female (sometimes with mosaicism), may be associated with genital tract abnormality
• If SRY region is present, fetus will be male
• Lack of follow-up for sexual development effects
• Some studies suggest mosaicism does not alter the risk for abnormality
• Presence or absence of mosaicism
• Proportion of cells
• Urgent parental chromosome analysis required
• If one parent is also carrying the ESAC and is phenotypically normal
• No increased risk of fetal abnormality
• If one parent has the ESAC in mosaic state
• Phenotype prediction is more difficult
• If one parent is a carrier of a balanced translocation of which the ESAC is a derivative
• Serious phenotypic abnormality is almost certain
• If de novo mosaic in CVS, get an amnio or blood sample
• Exclude abnormality confined to the placenta
• Ultrasound findings are helpful in prognostication
• Any abnormalities found will increase the risk of a clinical abnormal outcome
• Findings may assist in identifying origin of marker material
• UPD should be ruled out
• Abnormal MSS maybe
• Once marker material is identified:
• Extensive literature search for de novo marker for expected phenotype should be performed

References:

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

• Gardner RJM, Sutherland GR. Chromosome Abnormalities and Genetic Counseling. 2nd ed. Oxford University Press, USA; 1996.
• Starke H, Nietzel A, Weise A, et al. Small supernumerary marker chromosomes (SMCs): genotype-phenotype correlation and classification. Hum Genet. 2003;114(1):51-67.
• Marchina E, Piovani G, Vezzola L, et al. Molecular and cytogenetic characterization of extra-structurally abnormal chromosomes (ESACs) found prenatally: outcome and follow-up. Prenat Diagn. 2003;23(12):959-63.
• Hastings RJ, Nisbet DL, Waters K, Spencer T, Chitty LS. Prenatal detection of extra structurally abnormal chromosomes (ESACs): new cases and a review of the literature. Prenat Diagn. 1999;19(5):436-45.