Isochromosomes

i(Xq)

i(12p) – Pallister-Killian syndrome

i(9p)

i(18p)

Epidemiology and Etiology:

• Postzygotic most likely:
• Mosaicisms is very frequent
• Consider the possibility seriously even in level II mosaicism
• Some are formed form genetically identical arms, others are formed from homologous arms
• Most have genetically identical arms and are thought to form postzygotically
• Most are maternal in origin
• Reported isochromosomes:
• i(5p)
• i(8p)
• i(9p)
• i(12p)
• Pallister-Killian syndrome
• i(18p)
• i(21q)
• i(22q)
• i(Xq)
• acrocentric short arms
• supernumerary isochromosomes resulting in tetrasomy – almost exclusively:
• 9p
• 12p
• 18p
• Acrocentric short arms
• mechanism:
• centromere misdivision (classical mechanism):
• transverse division at the centromere during meiosis or mitosis
• resulting in i(Ap) and an i(Aq)
• molecular studies do not support; breakage and reunion events might occur predominantly within the area adjacent to the centromere; most are dicentric rather than monocentric
• Hairpin DNA structures thought to be important in generating double-stranded DNA breaks in i(17)(q10)
• Followed by NAHR event between repeats of opposite orientation on sister chromatids
• Generation of one dicentric and one acentric product
• somatic NAHR between non-sister chromatids
• U-loop (see Gardner, p. 265) formation (sister chromatid U-type exchange):
• U-loop formation near the centromere during DNA replication
• Endoreduplication forms 2 complete homologs:
• A dicentric isochromosome
• An acentric chromosome
• The acentric chromosome is lost
• The cell now has a 2 copies of the homologue plus an isochromosome of that homolog
• Mechanism similar to paracentric inversion recombination for i(X)(q10):
• ZXDA and ZXDB in proximal Xp just above centromere
• 98% homology, transcribing in opposite directions
• During X-to-X synapsis in meiosis:
• A small inversion loop occurs, enabling ZXDA to match up with ZXDB
• A cross-over occurs between the two ZXD loci
• Resulting isiodicentric chromosome Xqter->cen->ZXDA::ZXDA->cen->Xqter
• Other mechanisms are postulated

Common sites:

Gross features:

Histologic features:

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Molecular features:

Other features:

• Genetic counseling:
• Isochromosome mosaicism
• Chance of recurrence is very small (likely a post-zygotic event)
• Risk of UPD for de novo isochromosomes of 14 or 15 is 66%
• In all cases paternal UPD

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; 2004:616.