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Molecular cytogenetic characterisation of a mosaic add(12)(p13.3) with an inv dup(3)(q26.31 --> qter) detected in an autistic boy.

Carreira IM, Melo JB, Rodrigues C, Backx L, Vermeesch J, Weise A, Kosyakova N, Oliveira G, Matoso E - Mol Cytogenet (2009)

Bottom Line: Associated mosaicism could be the consequence of a post-zygotic event or could result from the correction of a trisomic conception.The mosaic terminal inv dup(3q) observed could be the result of two proposed alternative mechanisms.The present work further illustrates the advantages of the use of an integrative cytogenetic strategy, composed both by conventional and molecular techniques, on providing powerful information for an accurate diagnosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratório de Citogenética, Instituto de Biologia Médica e Centro de Neurociências e Biologia Celular, Faculdade de Medicina, Universidade de Coimbra, Portugal. i_marques@hotmail.com.

ABSTRACT

Background: Inverted duplications (inv dup) of a terminal chromosome region are a particular subset of rearrangements that often results in partial tetrasomy or partial trisomy when accompanied by a deleted chromosome. Associated mosaicism could be the consequence of a post-zygotic event or could result from the correction of a trisomic conception. Tetrasomies of distal segments of the chromosome 3q are rare genetic events and their phenotypic manifestations are diverse. To our knowledge, there are only 12 cases reported with partial 3q tetrasomy. Generally, individuals with this genomic imbalance present mild to severe developmental delay, facial dysmorphisms and skin pigmentary disorders.

Results: We present the results of the molecular cytogenetic characterization of an unbalanced mosaic karyotype consisting of mos 46,XY,add(12)(p13.3) [56]/46,XY [44] in a previously described 11 years old autistic boy, re-evaluated at adult age. The employment of fluorescence in situ hybridization (FISH) and multicolor banding (MCB) techniques identified the extra material on 12p to be derived from chromosome 3, defining the additional material on 12p as an inv dup(3)(qter --> q26.3::q26.3 --> qter). Subsequently, array-based comparative genomic hybridization (aCGH) confirmed the breakpoint at 3q26.31, defining the extra material with a length of 24.92 Mb to be between 174.37 and 199.29 Mb.

Conclusion: This is the thirteenth reported case of inversion-duplication 3q, being the first one described as an inv dup translocated onto a non-homologous chromosome. The mosaic terminal inv dup(3q) observed could be the result of two proposed alternative mechanisms. The most striking feature of this case is the autistic behavior of the proband, a characteristic not shared by any other patient with tetrasomy for 3q26.31 --> 3qter. The present work further illustrates the advantages of the use of an integrative cytogenetic strategy, composed both by conventional and molecular techniques, on providing powerful information for an accurate diagnosis. This report also highlights a chromosome region potentially involved in autistic disorders.

No MeSH data available.


Related in: MedlinePlus

Schematic representation showing the three mechanisms proposed for the formation and stabilization of the terminal inv dup 3q. A-B) Two possible mechanisms having in common a first step in gametogenesis with a double-strand break event at 3q, repaired by fusion of the two sister chromatids (U-loop) and giving rise to an acentric inv dup; A) Subsequent step would be the telomere capture from chromosome 12, a non-disjunction of the 12 homologous at meiosis I, leading to a gamete that after fertilization originated a trisomic zygote, that by cell rescue generated two cell lines; B) Other alternative mechanism would be the post-zygotic stabilization delay of the acentric inv dup; C) The third possibility is the generation of a terminal acentric inv dup as a result of a post-zygotic event at embryogenesis, which would necessarily lead to mosaicism.
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Figure 4: Schematic representation showing the three mechanisms proposed for the formation and stabilization of the terminal inv dup 3q. A-B) Two possible mechanisms having in common a first step in gametogenesis with a double-strand break event at 3q, repaired by fusion of the two sister chromatids (U-loop) and giving rise to an acentric inv dup; A) Subsequent step would be the telomere capture from chromosome 12, a non-disjunction of the 12 homologous at meiosis I, leading to a gamete that after fertilization originated a trisomic zygote, that by cell rescue generated two cell lines; B) Other alternative mechanism would be the post-zygotic stabilization delay of the acentric inv dup; C) The third possibility is the generation of a terminal acentric inv dup as a result of a post-zygotic event at embryogenesis, which would necessarily lead to mosaicism.

Mentions: Inverted duplications are a kind of genetic lesions that can appear either as mosaic, or non-mosaic, depending on the time that they are formed [18]. There are different well established mechanisms proposed for the origin of terminal inv dup. The present case, however, does not adjust entirely with the usual mechanisms proposed for terminal inv dup that would imply a concomitant deletion or a distal extra marker chromosome stabilized by neocentromerization. We propose three alternative mechanisms (Fig. 4A–C), two of them could have in common a first step in gametogenesis with a double-strand break event at 3q, repaired by fusion of the two sister chromatids (U-type exchange) and giving rise to an acentric inv dup (Fig. 4A–B). One possible mechanism for the subsequent step would be the healing by telomere capture from a non-homologous chromosome 12. A non-disjunction of the 12 homologous at meiosis I, led to the formation of a gamete that after fertilization originated a trisomic zygote, which included the der(12). In the first mitotic division, in an attempt of cell rescue, two cell lines would have been generated, by loosing either the der(12) or the normal 12 chromosome. A consequence of the heterodisomy generated by the segregation error at meiosis I could be a chromosome 12 uniparental disomy [19]. The other alternative mechanism (Fig. 4C) would be the generation of a terminal acentric inv dup either as a result of a post-zygotic mitotic division, which would necessarily lead to mosaicism, or at meiosis. In this case, the post-zygotic stabilization delay of the acentric inv dup, associated with the telomere capture from a non-homologous chromosome 12, could explain the mosaicism [7,20,21].


Molecular cytogenetic characterisation of a mosaic add(12)(p13.3) with an inv dup(3)(q26.31 --> qter) detected in an autistic boy.

Carreira IM, Melo JB, Rodrigues C, Backx L, Vermeesch J, Weise A, Kosyakova N, Oliveira G, Matoso E - Mol Cytogenet (2009)

Schematic representation showing the three mechanisms proposed for the formation and stabilization of the terminal inv dup 3q. A-B) Two possible mechanisms having in common a first step in gametogenesis with a double-strand break event at 3q, repaired by fusion of the two sister chromatids (U-loop) and giving rise to an acentric inv dup; A) Subsequent step would be the telomere capture from chromosome 12, a non-disjunction of the 12 homologous at meiosis I, leading to a gamete that after fertilization originated a trisomic zygote, that by cell rescue generated two cell lines; B) Other alternative mechanism would be the post-zygotic stabilization delay of the acentric inv dup; C) The third possibility is the generation of a terminal acentric inv dup as a result of a post-zygotic event at embryogenesis, which would necessarily lead to mosaicism.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2734522&req=5

Figure 4: Schematic representation showing the three mechanisms proposed for the formation and stabilization of the terminal inv dup 3q. A-B) Two possible mechanisms having in common a first step in gametogenesis with a double-strand break event at 3q, repaired by fusion of the two sister chromatids (U-loop) and giving rise to an acentric inv dup; A) Subsequent step would be the telomere capture from chromosome 12, a non-disjunction of the 12 homologous at meiosis I, leading to a gamete that after fertilization originated a trisomic zygote, that by cell rescue generated two cell lines; B) Other alternative mechanism would be the post-zygotic stabilization delay of the acentric inv dup; C) The third possibility is the generation of a terminal acentric inv dup as a result of a post-zygotic event at embryogenesis, which would necessarily lead to mosaicism.
Mentions: Inverted duplications are a kind of genetic lesions that can appear either as mosaic, or non-mosaic, depending on the time that they are formed [18]. There are different well established mechanisms proposed for the origin of terminal inv dup. The present case, however, does not adjust entirely with the usual mechanisms proposed for terminal inv dup that would imply a concomitant deletion or a distal extra marker chromosome stabilized by neocentromerization. We propose three alternative mechanisms (Fig. 4A–C), two of them could have in common a first step in gametogenesis with a double-strand break event at 3q, repaired by fusion of the two sister chromatids (U-type exchange) and giving rise to an acentric inv dup (Fig. 4A–B). One possible mechanism for the subsequent step would be the healing by telomere capture from a non-homologous chromosome 12. A non-disjunction of the 12 homologous at meiosis I, led to the formation of a gamete that after fertilization originated a trisomic zygote, which included the der(12). In the first mitotic division, in an attempt of cell rescue, two cell lines would have been generated, by loosing either the der(12) or the normal 12 chromosome. A consequence of the heterodisomy generated by the segregation error at meiosis I could be a chromosome 12 uniparental disomy [19]. The other alternative mechanism (Fig. 4C) would be the generation of a terminal acentric inv dup either as a result of a post-zygotic mitotic division, which would necessarily lead to mosaicism, or at meiosis. In this case, the post-zygotic stabilization delay of the acentric inv dup, associated with the telomere capture from a non-homologous chromosome 12, could explain the mosaicism [7,20,21].

Bottom Line: Associated mosaicism could be the consequence of a post-zygotic event or could result from the correction of a trisomic conception.The mosaic terminal inv dup(3q) observed could be the result of two proposed alternative mechanisms.The present work further illustrates the advantages of the use of an integrative cytogenetic strategy, composed both by conventional and molecular techniques, on providing powerful information for an accurate diagnosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratório de Citogenética, Instituto de Biologia Médica e Centro de Neurociências e Biologia Celular, Faculdade de Medicina, Universidade de Coimbra, Portugal. i_marques@hotmail.com.

ABSTRACT

Background: Inverted duplications (inv dup) of a terminal chromosome region are a particular subset of rearrangements that often results in partial tetrasomy or partial trisomy when accompanied by a deleted chromosome. Associated mosaicism could be the consequence of a post-zygotic event or could result from the correction of a trisomic conception. Tetrasomies of distal segments of the chromosome 3q are rare genetic events and their phenotypic manifestations are diverse. To our knowledge, there are only 12 cases reported with partial 3q tetrasomy. Generally, individuals with this genomic imbalance present mild to severe developmental delay, facial dysmorphisms and skin pigmentary disorders.

Results: We present the results of the molecular cytogenetic characterization of an unbalanced mosaic karyotype consisting of mos 46,XY,add(12)(p13.3) [56]/46,XY [44] in a previously described 11 years old autistic boy, re-evaluated at adult age. The employment of fluorescence in situ hybridization (FISH) and multicolor banding (MCB) techniques identified the extra material on 12p to be derived from chromosome 3, defining the additional material on 12p as an inv dup(3)(qter --> q26.3::q26.3 --> qter). Subsequently, array-based comparative genomic hybridization (aCGH) confirmed the breakpoint at 3q26.31, defining the extra material with a length of 24.92 Mb to be between 174.37 and 199.29 Mb.

Conclusion: This is the thirteenth reported case of inversion-duplication 3q, being the first one described as an inv dup translocated onto a non-homologous chromosome. The mosaic terminal inv dup(3q) observed could be the result of two proposed alternative mechanisms. The most striking feature of this case is the autistic behavior of the proband, a characteristic not shared by any other patient with tetrasomy for 3q26.31 --> 3qter. The present work further illustrates the advantages of the use of an integrative cytogenetic strategy, composed both by conventional and molecular techniques, on providing powerful information for an accurate diagnosis. This report also highlights a chromosome region potentially involved in autistic disorders.

No MeSH data available.


Related in: MedlinePlus