SNP array and FISH analysis of a proband with a 22q13.2- 22qter duplication shed light on the molecular origin of the rearrangement

Abstract

Background: In about one third of healthy subjects, the microscopic analysis of chromosomes reveals heteromorphisms with no clinical implications: for example changes in size of the short arm of acrocentric chromosomes. In patients with a pathological phenotype, however, a large acrocentric short arm can mask a genomic imbalance and should be investigated in more detail. We report the first case of a chromosome 22 with a large acrocentric short arm masking a partial trisomy of the distal long arm, characterized by SNP array. We suggest a possible molecular mechanism underlying the rearrangement.

Case presentation: We report the case of a 15-year-old dysmorphic girl with low grade psychomotor retardation characterized by a karyotype with a large acrocentric short arm of one chromosome 22. Cytogenetic analysis revealed a normal karyotype with a very intense Q-fluorescent and large satellite on the chromosome 22 short arm. Fluorescence in situ hybridisation analysis showed a de novo partial trisomy of the 22q13.2-qter chromosome region attached to the short arm of chromosome 22. SNP-array analysis showed that the duplication was 8.5 Mb long and originated from the paternal chromosome. Haplotype analysis revealed that the two paternal copies of the distal part of chromosome 22 have the same haplotype and, therefore, both originated from the same paternal chromosome 22. A possible molecular mechanism that could explain this scenario is a break-induced replication (BIR) which is involved in non-reciprocal translocation events.

Conclusion: The combined use of FISH and SNP arrays was crucial for a better understanding of the molecular mechanism underlying this rearrangement. This strategy could be applied for a better understanding of the molecular mechanisms underlying cryptic chromosomal rearrangements.

Fig. 1

Photographs of the patient at the age of 15. Frontal and lateral view of the proband showing mild dysmorphic traits

Fig. 2

Scatterplots of the relative B allele intensity signals. On the right, B allele intensity signals for the SNPs in the duplicated portion of chromosome 22 in the proband and her parents, respectively. On the left, the genotype assigned to each probe according to their B allele frequencies

Fig. 3

Cytogenetic and molecular analyses. a chromosome 22 QFQ banded karyotype of the patient. The red arrow points to the abnormal chromosome 22. b FISH analysis with probes for the subtelomeric region of chromosome 22q (in red). An additional signal located on the short arm of chromosome 22. c The derivative ideogram of the chromosome 22q13.2-qter duplication; d Array analysis. Copy number state of chromosome 22 probes inferred by CNAT and reported as number of copies

Fig. 4

Dual Colour FISH analyses. a FISH analysis with probes RP11-140I15 (green) and RP11-164E23 (red). In the proband, two additional hybridisation signals on the abnormal short arm of chromosome 22 are visible, whereas in the parents only two signals in the correct orientation are visible on the long arm of chr22. b FISH analysis with probes RP11-241G19 (green) and RP11-164E23 (red). The RP11-241G19 probe is located outside the duplicated region and displays only one hybridisation signal on the long arm of chr22 in all the subjects

Fig. 5

Mechanism proposed to explain the formation of a non-reciprocal translocation of the duplicated 22q13.2-qter region. The grey triangles are short regions of microhomology. In green and red are the distal portions of the 22p and 22q arms, respectively. The picture is not to scale. a A DSB eliminates the telomere of the short arm. b The 3′end proximal to the DSB invades a homolog sequence on the q arm and induces the formation of a mono-directional replication fork. The arrow indicates the direction of the replication fork. c-d The replication proceeds until the chromosome end is reached. e The distal portion of 22q (red) is duplicated and transposed inverted on 22p. See the discussion for details