Publication

Molecular Characterization of inv dup del(8p): Analysis of Five Cases

Abstract

We analyzed five patients with inverted duplication deletion of 8p [inv dup del(8p)] using fluorescence in situ hybridization (FISH) and short tandem repeat polymorphism (STRP) analysis. In all patients, inv dup del(8p) consisted of a deleted distal segment, an intact in-between segment, and a duplicated proximal segment. In all of them, the proximal breakpoint of the deletion and one of the breakpoints of the duplication were identical, each located at one of the two olfactory receptor gene clusters at 8p23. FISH analysis showed all their mothers to be heterozygous carriers of an 8p23 inversion [inv(8)(p23)]. STRP analysis indicated that the deletions occurred in maternally derived chromosomes. The duplicated segments had two copies of maternal, either heterozygous or homozygous alleles. These findings support and reinforce those in 16 patients with inv dup del(8p) and their parents by Floridia et al. [1996: Am J Hum Genet 58:785–796] and subsequent additional studies of 10 of them by Giglio et al. [2001: Am J Hum Genet 68:874–883]. Based on these findings, we propose a model for the inv dup del(8p) formation. The inverted segment and its normal counterpart in inv(8)(p23) heterozygous carrier mothers form a loop at the pachytene period of meiosis I. Inv dup del(8p) with heterozygous duplication is formed through at least one meiotic recombination within the loop. Inv dup del(8p) with the homozygous duplication arises through two meiotic recombinations on the inv(8)(p23) chromosome (one within the loop and the other between the loop and centromere). Subsequent rescue by eliminating a part of the duplicated segment and a centromere enables formation of viable inv dup del(8p). The frequency of the inv(8)(p23) allele is 39% in a normal Japanese population, comparable to 26% in Europeans Giglio et al. [2001: Am J Hum Genet 68:874–883]. The proposed mechanism of formation of inv dup del(8p) requires two independent events (a recombination within the loop and subsequent rescue), which may explain its rarity.

Citation

The Project 8p Foundation (Project 8p) was created in 2018 to:

  • Accelerate future treatments, not only for 8p, but potentially for other chromosome-wide diseases as well.
  • Lead with knowledge from patients. Currently, there is no cure for 8p disorders, nor is there a standard course of treatment.

The Project 8p Foundation (Project 8p) was created in 2018 to:

  • Raise transformative funding for pioneering scientific research into treatments for a complex, rare disease involving 250+ affected genes on the short arm of the 8 th chromosome (8p). Rearrangements of these genes causes significant abnormalities to the entire neurological system, thus all organs and functions of the body– with variance in cognitive functions, gross motor skills, social development and other challenges during infancy, and throughout life;
  • Empower a unified community of 8p patients and their families so they can have meaningful lives today; and
  • Accelerate future treatments, not only for 8p, but potentially for other chromosome-wide diseases as well.