Common structural features characterize interstitial intrachromosomal Xp and 18q triplications

Abstract

Rare intrachromosomal triplications producing partial tetrasomies have been reported for a number of chromosomes. A detailed molecular characterization, necessary to define the mechanism of their formation, has so far been lacking. We report on the detailed clinical, cytogenetic, and molecular characterization of two triplications, one de novo involving chromosome 18q, the other familial on chromosome Xp. The clinical phenotype of the patient with 18q triplication, very likely due to overexpression of one or more of the genes in the region, consists mainly of facial dysmorphisms and developmental delay. The familial Xp triplication does not cause an increase in the number of copies of any gene and is almost certainly a polymorphism. The rearrangements are actually complex duplications/triplications. In both patients, their proximal breakpoints are located within complex segmental duplications, one containing the VCX gene cluster on chromosome Xp, the other the TCEB3 genes on chromosome 18q. A proximal duplicated region is also present in both patients. All junctions we analyzed were formed by non-homologous end joining (NHEJ). The structural features shared between our patients suggest the involvement of a common mechanism in the genesis of interstitial intrachromosomal triplications.

Combined deletion 18q22.2 and duplication/triplication 18q22.1 causes microcephaly, mental retardation and leukencephalopathy

“…The location of the duplication proximal to the triplication in our patient is in line with previous reports of intrachromosomal triplications and supports the theory of a common mechanism in the genesis of interstitial intrachromosomal triplications (Giorda et al, 2011). The duplication/triplication in our patient furthermore corresponds to a proposed critical region on chromosome 18q for appearance of the Edwards syndrome phenotype (Fig.…”

“…A combined deletion and duplication/triplication of 18q is rare and can be found in only 6% of patients with 18q deletions (Heard et al, 2009), while simple interstitial deletions and simple terminal deletions occur in 15% and 69% of patients with 18q deletions, respectively. A triplication of 18q has only been described once before (Giorda et al, 2011).…”

Low-copy repeats at the human VIPR2 gene predispose to recurrent and nonrecurrent rearrangements

“…We previously demonstrated the same arrangement in two larger nonrecurrent rearrangements and pointed out for the first time the presence of both duplicated and triplicated portions. 24 To explain the genesis of complex triplications, it was suggested that intrachromosomal triplications can arise from a dicentric, inverted duplicated chromosome. 25 Breakage of the dicentric chromosome and recombination with a normal chromosome would lead to triplication.…”

Next-Generation Sequencing of Duplication CNVs Reveals that Most Are Tandem and Some Create Fusion Genes at Breakpoints

“…30,[44][45][46][47][48] In most cases, the triplicated segment is inverted relative to the tandem duplication, and this conformation is known as DUP-TRP/INV-DUP. Breakpoint analysis of six DUP-TRP-DUPs in our study revealed that half of the triplications are in direct orientation and half are inverted relative to the duplication (Table S7).…”