Genomic profile of copy number variants on the short arm of human chromosome 8

Abstract

We evaluated 966 consecutive pediatric patients with various developmental disorders by high-resolution microarray-based comparative genomic hybridization and found 10 individuals with pathogenic copy number variants (CNVs) on the short arm of chromosome 8 (8p), representing approximately 1% of the patients analyzed. Two patients with 8p terminal deletion associated with interstitial inverted duplication (inv dup del(8p)) had different mechanisms leading to the formation of a dicentric intermediate during meiosis. Three probands carried an identical ∼5.0 Mb interstitial duplication of chromosome 8p23.1. Four possible hotspots within 8p were observed at nucleotide coordinates of ∼10.45, 24.32-24.82, 32.19-32.77, and 38.94-39.72 Mb involving the formation of recurrent genomic rearrangements. Other CNVs with deletion- or duplication-specific start or stop coordinates on the 8p provide useful information for exploring the basic mechanisms of complex structural rearrangements in the human genome.

Figure 1

Locations of genomic abnormalities identified on chromosome 8p in this study. Numbers 1–10 represent the two patients with genomic abnormalities on chromosome 8p.

Figure 2

Distribution of benign copy number variants (CNVs) across 8p. Each dot represents a single benign CNV.

Figure 3

(a) Mechanism 1 in which the chromosome carrying the paracentric inversion between REPD and REPP pairs with its homologue by forming an inversion loop. Crossing-over and recombination within the loop create an unstable dicentric chromosome and an acentric fragment. The dicentric chromosome breaks outside the inverted region lead to the formation of a monocentric chromosome with a terminal deletion and an inverted duplication with a single copy region between the duplication. (b) Mechanism 2 in which the inverted LCRs within REPD or REPP in the same short arm of chromosome 8. Pairing and recombination between the inverted repeats on sister chromatids results in the formation of a dicentric chromosome and an acentric fragment. Breakage of the dicentric outside the inverted repeats leads to a monocentric chromosome with a terminal deletion and an inverted duplication with a single copy region between the duplication, which will be flanked by the inverted repeats. (c) Mechanism 3, which involves an initial premeiotic double-strand break of the two sister chromatids. Fusion of the broken ends results in a symmetric U-type reunion between the sister chromatids leading to the formation of a dicentric chromosome. Breakage distal to the fusion site outside the fusion region results in a monocentric chromosome with a terminal deletion and an inverted duplication without a single copy region between the duplication.