Pure 16q21q22.1 deletion in a complex rearrangement possibly caused by a chromothripsis event

Abstract

Background: Partial monosomies of chromosome 16q are rare and overlapping effects from complex chromosomal rearrangements often hamper genotype-phenotype correlations for such imbalances. Here, we report the clinical features of an isolated partial monosomy 16q21q22.1 in a boy with a complex de novo rearrangement possibly resulting from a chromothripsis event.

Results: The patient presented with low birth weight, microcephaly, developmental delay, facial dysmorphisms, short stature, dysmorphic ears and cardiopathy. Standard and molecular cytogenetics showed a complex rearrangement characterised by a pericentromeric inversion in one of chromosomes 12 and an inverted insertional translocation of the 12q14q21.1 region, from the rearranged chromosome 12, into the q21q22.1 tract of a chromosome 16. Array-CGH analysis unravelled a partial 16q21q22.1 monosomy, localised in the rearranged chromosome 16.

Conclusions: The comparison of the present case to other 16q21q22 monosomies contributed to narrow down the critical region for cardiac anomalies in the 16q22 deletion syndrome. However, more cases, well characterised both for phenotypic signs and genomic details, are needed to further restrict candidate regions for phenotypic signs in 16q deletions. The present case also provided evidence that a very complex rearrangement, possibly caused by a chromothripsis event, might be hidden behind a classical phenotype that is specific for a syndrome.

Figure 1

The boy at the age of 1 year. Note low set ears, epicanthus and thin upper-lip.

Figure 2

G-Banding image of rearranged chromosomes 12 and 16. G-Banded karyotype shows a pericentric inversion, from band p12 to q13, on one chromosome 12, an interstitial deletion of the region from 12q14 to 12q21 and additional material on one chromosome 16, within the bands q21q22. Arrows mark the derivative chromosomes.

Figure 3

Dual colour fluorescence in situ hybridization analysis of chromosome 16 and chromosome 12. FISH analysis using wcp12 (green) and wcp16 (red) probes (a) or RP11-485K18 (red) BAC probe, mapping to 12p11.2 and CEP12 (green), used as control probe (b), showed that the additional material present in the q arm of one chromosome 16 was derived from chromosome 12 and confirmed the pericentric inversion of one chromosome 12.

Figure 4

High resolution multicolour banding (MCB). High resolution MCB image of the normal chromosome 12 compared to the rearranged chromosome 12 shows that the pericentric inversion extended from the band 12p12 to the band 12q14. Chromosome 16 image shows an inverted insertion of the 12q14q21 region inside the tract 16q21q22.

Figure 5

Array-CGH analysis. The analysis shows a partial deletion of the 16q21q22.1 tract, spanning approximately 2.1 Mb (chr16:65713516–67842736 [Hg19]), involving the region in which the 12q14q21.1 tract was inserted.

Figure 6

Overlapping of 16q21q22 deletions. The figure shows the present case (blue line), the patients described by Yamamoto et al. [1] (black line), by Goto et al. [13] (pink line), by Tsoutsou et al. [5] (yellow line), the DECIPHER cases 2150 (purple line) and 249502 (brown line) and the asymptomatic region described by Coussement et al. [3] (green line).

Figure 7

Schematic representation of possible mechanisms cause of the complex chromosomal rearrangement in the proband. DNA double-strand breaks are formed as a result of "chromosome shattering" (triangles blacks) with the corresponding formation of chromosomal fragments that are rearranged through the phenomenon of "chromosome reassembly". The result is the formation of inversions (inv, blue arrows), deletions (the black arrow) and insertional translocation (IT, green dashed arrow) that originate the two derivative chromosomes: chromosome 12 with a pericentric inversion and deletion of 12q14q21.1 and chromosome 16 with the concomitant insertion of the 12q14q21.1 region with inverted sense in place of the 16q21-22.1 region that is deleted.