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A 15 Mb large paracentric chromosome 21 inversion identified in Czech population through a pair of flanking duplications.

Drabova J, Trkova M, Hancarova M, Novotna D, Hejtmankova M, Havlovicova M, Sedlacek Z - Mol Cytogenet (2014)

Bottom Line: Three out of the total of about 4000 chromosomes 21 examined in our sample carried the duplications and were inverted, corresponding to carrier frequency of about 1/660.The inverted segment carried an identical shared haplotype in the three families studied.The haplotypes, however, diverged very rapidly in the flanking regions, possibly pointing to an ancient founder event at the origin of the inversion.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.

ABSTRACT

Background: Inversions are balanced structural chromosome rearrangements, which can influence gene expression and the risk of unbalanced chromosome constitution in offspring. Many examples of inversion polymorphisms exist in human, affecting both heterochromatic regions and euchromatin.

Results: We describe a novel, 15 Mb long paracentric inversion, inv(21)(q21.1q22.11), affecting more than a third of human 21q. Despite of its length, the inversion cannot be detected using karyotyping due to similar band patterns on the normal and inverted chromosomes, and is therefore likely to escape attention. Its identification was aided by the repeated observation of the same pair of 150 kb long duplications present in cis on chromosome 21 in three Czech families subjected to microarray analysis. The finding prompted us to hypothesise that this co-occurrence of two remote duplications could be associated with an inversion of the intervening segment, and this speculation turned out to be right. The inversion was confirmed in a series of FISH experiments which also showed that the second copy of each of the duplications was always located at the opposite end of the inversion. The presence of the same pair of duplications in additional individuals reported in public databases indicates that the inversion may also be present in other populations. Three out of the total of about 4000 chromosomes 21 examined in our sample carried the duplications and were inverted, corresponding to carrier frequency of about 1/660. Although the breakpoints affect protein-coding genes, the occurrence of the inversion in normal parents and siblings of our patients and the occurrence of the duplications in unaffected controls in databases indicate that this rare variant is rather non-pathogenic. The inverted segment carried an identical shared haplotype in the three families studied. The haplotypes, however, diverged very rapidly in the flanking regions, possibly pointing to an ancient founder event at the origin of the inversion.

Conclusions: The identification of inv(21)(q21.1q22.11) supports the notion that paracentric inversions are the most common form of chromosomal variation and that some of them may still remain undetected.

No MeSH data available.


Related in: MedlinePlus

An example of the SNP array result in a chr21 duplication carrier and gene content of the two concurrent chr21 duplications. LRR, log R ratio; BAF, B allele frequency. Thick and thin blue bars in the schematics represent the minimum and maximum span of the duplications, respectively. Vertical double lines mark the regions of the duplications. Open arrows show the position and orientation of genes. Chromosome 21 megabase scale is also added.
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Figure 1: An example of the SNP array result in a chr21 duplication carrier and gene content of the two concurrent chr21 duplications. LRR, log R ratio; BAF, B allele frequency. Thick and thin blue bars in the schematics represent the minimum and maximum span of the duplications, respectively. Vertical double lines mark the regions of the duplications. Open arrows show the position and orientation of genes. Chromosome 21 megabase scale is also added.

Mentions: Families A-C were referred for genetic testing because of intellectual disability (ID), autism and other phenotypes in their children. Karyotyping of the family members showed apparently normal results. SNP array analysis identified similar pairs of duplications on chr21 of about 150 kb each located in a distance of about 15 Mb initially in the affected children from Families A and B and in an unaffected sibling from Family C. Later the same pairs of duplications were also identified in an unaffected father from Family A and in unaffected mothers from Families B and C. Automated analysis followed by manual inspection showed that the breakpoint intervals of both duplications were identical in all six carriers (arr 21q21.1(16,957,141×2, 16,988,490-17,146,328×3, 17,166,671×2) and arr 21q22.11(32,080,968×2, 32,086,323-32,236,820×3, 32,242,774×2)). The proximal duplication involved the 5' region of the USP25 gene including three to five of its 5' exons. The distal duplication was located in the KRTAP cluster and contained five members of this gene family (KRTAP21-3, KRTAP21-2, KRTAP21-1, KRTAP8-1 and KRTAP7-1) (Figure 1). The breakpoint intervals did not contain segmental duplications or any remarkable enrichment for dispersed repeats. With the exception of common polymorphisms, no additional significant CNVs were found in the individuals tested from Families A-C.


A 15 Mb large paracentric chromosome 21 inversion identified in Czech population through a pair of flanking duplications.

Drabova J, Trkova M, Hancarova M, Novotna D, Hejtmankova M, Havlovicova M, Sedlacek Z - Mol Cytogenet (2014)

An example of the SNP array result in a chr21 duplication carrier and gene content of the two concurrent chr21 duplications. LRR, log R ratio; BAF, B allele frequency. Thick and thin blue bars in the schematics represent the minimum and maximum span of the duplications, respectively. Vertical double lines mark the regions of the duplications. Open arrows show the position and orientation of genes. Chromosome 21 megabase scale is also added.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4236861&req=5

Figure 1: An example of the SNP array result in a chr21 duplication carrier and gene content of the two concurrent chr21 duplications. LRR, log R ratio; BAF, B allele frequency. Thick and thin blue bars in the schematics represent the minimum and maximum span of the duplications, respectively. Vertical double lines mark the regions of the duplications. Open arrows show the position and orientation of genes. Chromosome 21 megabase scale is also added.
Mentions: Families A-C were referred for genetic testing because of intellectual disability (ID), autism and other phenotypes in their children. Karyotyping of the family members showed apparently normal results. SNP array analysis identified similar pairs of duplications on chr21 of about 150 kb each located in a distance of about 15 Mb initially in the affected children from Families A and B and in an unaffected sibling from Family C. Later the same pairs of duplications were also identified in an unaffected father from Family A and in unaffected mothers from Families B and C. Automated analysis followed by manual inspection showed that the breakpoint intervals of both duplications were identical in all six carriers (arr 21q21.1(16,957,141×2, 16,988,490-17,146,328×3, 17,166,671×2) and arr 21q22.11(32,080,968×2, 32,086,323-32,236,820×3, 32,242,774×2)). The proximal duplication involved the 5' region of the USP25 gene including three to five of its 5' exons. The distal duplication was located in the KRTAP cluster and contained five members of this gene family (KRTAP21-3, KRTAP21-2, KRTAP21-1, KRTAP8-1 and KRTAP7-1) (Figure 1). The breakpoint intervals did not contain segmental duplications or any remarkable enrichment for dispersed repeats. With the exception of common polymorphisms, no additional significant CNVs were found in the individuals tested from Families A-C.

Bottom Line: Three out of the total of about 4000 chromosomes 21 examined in our sample carried the duplications and were inverted, corresponding to carrier frequency of about 1/660.The inverted segment carried an identical shared haplotype in the three families studied.The haplotypes, however, diverged very rapidly in the flanking regions, possibly pointing to an ancient founder event at the origin of the inversion.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.

ABSTRACT

Background: Inversions are balanced structural chromosome rearrangements, which can influence gene expression and the risk of unbalanced chromosome constitution in offspring. Many examples of inversion polymorphisms exist in human, affecting both heterochromatic regions and euchromatin.

Results: We describe a novel, 15 Mb long paracentric inversion, inv(21)(q21.1q22.11), affecting more than a third of human 21q. Despite of its length, the inversion cannot be detected using karyotyping due to similar band patterns on the normal and inverted chromosomes, and is therefore likely to escape attention. Its identification was aided by the repeated observation of the same pair of 150 kb long duplications present in cis on chromosome 21 in three Czech families subjected to microarray analysis. The finding prompted us to hypothesise that this co-occurrence of two remote duplications could be associated with an inversion of the intervening segment, and this speculation turned out to be right. The inversion was confirmed in a series of FISH experiments which also showed that the second copy of each of the duplications was always located at the opposite end of the inversion. The presence of the same pair of duplications in additional individuals reported in public databases indicates that the inversion may also be present in other populations. Three out of the total of about 4000 chromosomes 21 examined in our sample carried the duplications and were inverted, corresponding to carrier frequency of about 1/660. Although the breakpoints affect protein-coding genes, the occurrence of the inversion in normal parents and siblings of our patients and the occurrence of the duplications in unaffected controls in databases indicate that this rare variant is rather non-pathogenic. The inverted segment carried an identical shared haplotype in the three families studied. The haplotypes, however, diverged very rapidly in the flanking regions, possibly pointing to an ancient founder event at the origin of the inversion.

Conclusions: The identification of inv(21)(q21.1q22.11) supports the notion that paracentric inversions are the most common form of chromosomal variation and that some of them may still remain undetected.

No MeSH data available.


Related in: MedlinePlus