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

Magri C, Marchina E, Bertini V, Traversa M, Savio G, Pilotta A, Piovani G - BMC Med. Genet. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Biology and Genetics Division, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy. chiara.magri@unibs.it.

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.

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Related in: MedlinePlus

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
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Fig4: 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

Mentions: FISH with telomere set probes revealed an additional positive hybridisation signal of the specific subtelomere probe of the 22 chromosome long arm on the large satellite of the short arm of chromosome 22 (Fig. 3b). To rule out the presence of cryptic imbalances in the genome and to confirm our results, we performed further investigations using BAC clones (RP-11) specific for different regions of chromosome 22q13.2 to characterize the duplicated region. Dual-colour FISH with BAC clones RP11-140I15 and RP11-164E23 showed two hybridisation signals on the abnormal short arm of chromosome 22, whereas dual-colour FISH with BAC clones RP11-241G19 and RP11-164E23 revealed only one hybridisation signal of BAC RP11-164E23 on the abnormal short arm of chromosome 22. Based on these findings, we determined the karyotype to be: 46,XX, ish der(22)(qter → q13.2::p11 → qter) [21], (Fig. 3c). FISH with telomeric and with the same BAC clones revealed normal results in the parents: no rearranged or inverted cryptic duplicated regions were highlighted (Fig. 4).Fig. 4


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

Magri C, Marchina E, Bertini V, Traversa M, Savio G, Pilotta A, Piovani G - BMC Med. Genet. (2015)

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
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4557606&req=5

Fig4: 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
Mentions: FISH with telomere set probes revealed an additional positive hybridisation signal of the specific subtelomere probe of the 22 chromosome long arm on the large satellite of the short arm of chromosome 22 (Fig. 3b). To rule out the presence of cryptic imbalances in the genome and to confirm our results, we performed further investigations using BAC clones (RP-11) specific for different regions of chromosome 22q13.2 to characterize the duplicated region. Dual-colour FISH with BAC clones RP11-140I15 and RP11-164E23 showed two hybridisation signals on the abnormal short arm of chromosome 22, whereas dual-colour FISH with BAC clones RP11-241G19 and RP11-164E23 revealed only one hybridisation signal of BAC RP11-164E23 on the abnormal short arm of chromosome 22. Based on these findings, we determined the karyotype to be: 46,XX, ish der(22)(qter → q13.2::p11 → qter) [21], (Fig. 3c). FISH with telomeric and with the same BAC clones revealed normal results in the parents: no rearranged or inverted cryptic duplicated regions were highlighted (Fig. 4).Fig. 4

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Biology and Genetics Division, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy. chiara.magri@unibs.it.

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.

Show MeSH
Related in: MedlinePlus