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Niels Tommerup - One of the best experts on this subject based on the ideXlab platform.
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cryptic breakpoint identified by whole genome mate pair sequencing in a rare paternally inherited complex Chromosomal Rearrangement
Molecular Cytogenetics, 2018Co-Authors: Constantia Aristidou, Athina Theodosiou, Andria Ketoni, Mads Bak, Mana M. Mehrjouy, Niels Tommerup, Carolina SismaniAbstract:Precise characterization of apparently balanced complex Chromosomal Rearrangements in non-affected individuals is crucial as they may result in reproductive failure, recurrent miscarriages or affected offspring. We present a family, where the non-affected father and daughter were found, using FISH and karyotyping, to be carriers of a three-way complex Chromosomal Rearrangement [t(6;7;10)(q16.2;q34;q26.1), de novo in the father]. The family suffered from two stillbirths, one miscarriage, and has a son with severe intellectual disability. In the present study, the family was revisited using whole-genome mate-pair sequencing. Interestingly, whole-genome mate-pair sequencing revealed a cryptic breakpoint on derivative (der) chromosome 6 rendering the Rearrangement even more complex. FISH using a chromosome (chr) 6 custom-designed probe and a chr10 control probe confirmed that the interstitial chr6 segment, created by the two chr6 breakpoints, was translocated onto der(10). Breakpoints were successfully validated with Sanger sequencing, and small imbalances as well as microhomology were identified. Finally, the complex Chromosomal Rearrangement breakpoints disrupted the SIM1, GRIK2, CNTNAP2, and PTPRE genes without causing any phenotype development. In contrast to the majority of maternally transmitted complex Chromosomal Rearrangement cases, our study investigated a rare case where a complex Chromosomal Rearrangement, which most probably resulted from a Type IV hexavalent during the pachytene stage of meiosis I, was stably transmitted from a fertile father to his non-affected daughter. Whole-genome mate-pair sequencing proved highly successful in identifying cryptic complexity, which consequently provided further insight into the meiotic segregation of chromosomes and the increased reproductive risk in individuals carrying the specific complex Chromosomal Rearrangement. We propose that such complex Rearrangements should be characterized in detail using a combination of conventional cytogenetic and NGS-based approaches to aid in better prenatal preimplantation genetic diagnosis and counseling in couples with reproductive problems.
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Cryptic breakpoint identified by whole-genome mate-pair sequencing in a rare paternally inherited complex Chromosomal Rearrangement
BMC, 2018Co-Authors: Constantia Aristidou, Athina Theodosiou, Andria Ketoni, Mads Bak, Mana M. Mehrjouy, Niels Tommerup, Carolina SismaniAbstract:Abstract Background Precise characterization of apparently balanced complex Chromosomal Rearrangements in non-affected individuals is crucial as they may result in reproductive failure, recurrent miscarriages or affected offspring. Case presentation We present a family, where the non-affected father and daughter were found, using FISH and karyotyping, to be carriers of a three-way complex Chromosomal Rearrangement [t(6;7;10)(q16.2;q34;q26.1), de novo in the father]. The family suffered from two stillbirths, one miscarriage, and has a son with severe intellectual disability. In the present study, the family was revisited using whole-genome mate-pair sequencing. Interestingly, whole-genome mate-pair sequencing revealed a cryptic breakpoint on derivative (der) chromosome 6 rendering the Rearrangement even more complex. FISH using a chromosome (chr) 6 custom-designed probe and a chr10 control probe confirmed that the interstitial chr6 segment, created by the two chr6 breakpoints, was translocated onto der(10). Breakpoints were successfully validated with Sanger sequencing, and small imbalances as well as microhomology were identified. Finally, the complex Chromosomal Rearrangement breakpoints disrupted the SIM1, GRIK2, CNTNAP2, and PTPRE genes without causing any phenotype development. Conclusions In contrast to the majority of maternally transmitted complex Chromosomal Rearrangement cases, our study investigated a rare case where a complex Chromosomal Rearrangement, which most probably resulted from a Type IV hexavalent during the pachytene stage of meiosis I, was stably transmitted from a fertile father to his non-affected daughter. Whole-genome mate-pair sequencing proved highly successful in identifying cryptic complexity, which consequently provided further insight into the meiotic segregation of chromosomes and the increased reproductive risk in individuals carrying the specific complex Chromosomal Rearrangement. We propose that such complex Rearrangements should be characterized in detail using a combination of conventional cytogenetic and NGS-based approaches to aid in better prenatal preimplantation genetic diagnosis and counseling in couples with reproductive problems
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genetic counseling in adult carriers of a balanced Chromosomal Rearrangement ascertained in childhood experiences from a nationwide reexamination of translocation carriers
Genetics in Medicine, 2007Co-Authors: Iben Bache, Karen Brondumnielsen, Niels TommerupAbstract:Purpose: Prenatal diagnosis is offered to carriers of a balanced Chromosomal Rearrangement because it may predispose to offspring with an unbalanced karyotype. Therefore, carriers examined prenatally or in childhood should be informed before they reach reproductive age. We aimed to determine how many of the adult carriers ascertained in childhood currently know about their carrier status. Methods: We used data obtained by a questionnaire study reexamining carriers of a balanced reciprocal translocation. When a carrier was older than 18 years of age and had been examined in childhood, relatives were asked whether she/he knew of the translocation. Results: Among the 113 parents we interviewed, 10 carriers (9%) in 8 families had not been informed. In one of the eight families, an offspring with an unbalanced translocation was born 23 years after the father had been examined in childhood. Conclusion: Because of our findings, the practice of genetic counseling in Denmark has been changed: When a carrier of a balanced Chromosomal Rearrangement who was examined prenatally or in childhood turns 18 years of age, the parents will receive a letter reminding the family about the reproductive risk.
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population based study of cancer among carriers of a constitutional structural Chromosomal Rearrangement
Genes Chromosomes and Cancer, 2006Co-Authors: Iben Bache, Niels Tommerup, Henrik Hasle, Jorgen H OlsenAbstract:We measured the occurrence of cancer in an unselected cohort of carriers of constitutional structural Rearrangements in virtually complete nationwide registries for cancer and constitutional cytogenetic abnormalities. We identified 4,816 carriers of a constitutional structural Rearrangement in the Danish Cytogenetic Registry and searched for cancer diagnoses by linkage to the Danish Cancer Registry. There was no overall increased risk for cancer among carriers (standardized incidence ratio [SIR], 0.96; 95% confidence interval [CI], 0.84-1.10), and no significant difference from that expected was found in balanced and unbalanced Rearrangements or in any subtypes of Rearrangements. We found significantly lower risks for carriers with Rearrangements involving chromosome 21 (SIR, 0.50; 95% CI, 0.22-0.99) and for paternally inherited Rearrangements (SIR, 0.30; 95% CI, 0.06-0.88). Risk estimates for the observed type-specific cancers showed an increased risk for non-Hodgkin lymphoma (SIR, 2.11; 95% CI, 1.09-3.69). However, subgroup analyses were not guided by study hypotheses, and our statistical evaluation of the data should be looked upon as exploratory. In addition, we found 12 constitutional structural Rearrangements with a breakpoint potentially associated with a cancer-related gene. Potential new loci associated with type-specific cancers were suggested by the findings of families with more than one affected carrier and by the involvement of the same cytogenetic bands in unrelated carriers. Molecular mapping of these breakpoints might provide new insight into cancer predisposition.
James Lespinasse - One of the best experts on this subject based on the ideXlab platform.
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de novo complex Chromosomal Rearrangements ccr involving chromosome 1 5 and 6 resulting in microdeletion for 6q14 in a female carrier with psychotic disorder
American Journal of Medical Genetics Part A, 2004Co-Authors: James Lespinasse, M O North, Merete Bugge, M O Rethore, Claes Lundsteen, Maria KirchhoffAbstract:A 23-year-old obese woman with a psychotic disorder was found to have a de novo apparently balanced complex Chromosomal Rearrangement involving chromosomes 1, 5, and 6. Molecular cytogenetic analyses using high-resolution comparative genomic hybridization (HR-CGH) showed a microdeletion at 6q14 in a der(6). Application of HR-CGH facilitated detection of micro-Rearrangement of all de novo apparently balanced complex Chromosomal Rearrangements (CCR) and supported the localization of the breakpoint. According to our knowledge, no constitutional interstitial microdeletion of chromosome 6q14 has been found associated with a schizoid-type phenotype.
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a balanced complex Chromosomal Rearrangement bccr in a family with reproductive failure
Human Reproduction, 2003Co-Authors: James Lespinasse, M O North, C Paravy, M J Brunel, P Malzac, J L BlouinAbstract:Balanced complex Chromosomal Rearrangements are very rare events in the human population. Translocations involving three or more chromosomes frequently lead to a severe reproductive impairment secondary to meiotic disturbance in males and to Chromosomal imbalance in gametes of females. We report a new familial case of complex chromosome anomaly involving chromosomes 13, 14 and 22. Cytogenetic investigations showed a complex Chromosomal chromosome Rearrangement involving: (i) a Robertsonian translocation between chromosomes 13 and 14; and (ii) a reciprocal translocation between the long arms of chromosome 14 and the long arm of chromosome 22. The aetiology of the translocation was characterized by conventional fluorescence in-situ hybridization (FISH) studies and routine R- and G-banding (RTBG and GBTG) combined with alpha and beta satellite centromeric FISH probes. Predicted configuration of the hexavalent at pachytene stage of meiosis was used to consider the modes of segregation; only two configurations resulted in a normal or balanced gamete karyotype. Reproductive management and genetic counselling are discussed.
Paloma Garciabellido - One of the best experts on this subject based on the ideXlab platform.
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language impairment in a case of a complex Chromosomal Rearrangement with a breakpoint downstream of foxp2
Molecular Cytogenetics, 2015Co-Authors: Daniela Moralli, Ron Nudel, May T M Chan, Catherine M Green, Emanuela V Volpi, Antonio Benitezburraco, Dianne F Newbury, Paloma GarciabellidoAbstract:Background We report on a young female, who presents with a severe speech and language disorder and a balanced de novo complex Chromosomal Rearrangement, likely to have resulted from a chromosome 7 pericentromeric inversion, followed by a chromosome 7 and 11 translocation.
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language impairment in a case of a complex Chromosomal Rearrangement with a breakpoint downstream of foxp2
Molecular Cytogenetics, 2015Co-Authors: Daniela Moralli, Ron Nudel, May T M Chan, Catherine M Green, Emanuela V Volpi, Antonio Benitezburraco, Dianne F Newbury, Paloma GarciabellidoAbstract:Background: We report on a young female, who presents with a severe speech and language disorder and a balanced de novo complex Chromosomal Rearrangement, likely to have resulted from a chromosome 7 pericentromeric inversion, followed by a chromosome 7 and 11 translocation. Results: Using molecular cytogenetics, we mapped the four breakpoints to 7p21.1-15.3 (chromosome position: 20,954,043-21,001,537, hg19), 7q31 (chromosome position: 114,528,369-114,556,605, hg19), 7q21.3 (chromosome position: 93,884,065-93,933,453, hg19) and 11p12 (chromosome position: 38,601,145-38,621,572, hg19). These regions contain only non-coding transcripts (ENSG00000232790 on 7p21.1 and TCONS_00013886, TCONS_00013887, TCONS_00014353, TCONS_00013888 on 7q21) indicating that no coding sequences are directly disrupted. The breakpoint on 7q31 mapped 200 kb downstream of FOXP2, a well-known language gene. No splice site or non-synonymous coding variants were found in the FOXP2 coding sequence. We were unable to detect any changes in the expression level of FOXP2 in fibroblast cells derived from the proband, although this may be the result of the low expression level of FOXP2 in these cells. Conclusions: We conclude that the phenotype observed in this patient either arises from a subtle change in FOXP2 regulation due to the disruption of a downstream element controlling its expression, or from the direct disruption of non-coding RNAs.
Antonio Benitezburraco - One of the best experts on this subject based on the ideXlab platform.
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language impairment in a case of a complex Chromosomal Rearrangement with a breakpoint downstream of foxp2
Molecular Cytogenetics, 2015Co-Authors: Daniela Moralli, Ron Nudel, May T M Chan, Catherine M Green, Emanuela V Volpi, Antonio Benitezburraco, Dianne F Newbury, Paloma GarciabellidoAbstract:Background We report on a young female, who presents with a severe speech and language disorder and a balanced de novo complex Chromosomal Rearrangement, likely to have resulted from a chromosome 7 pericentromeric inversion, followed by a chromosome 7 and 11 translocation.
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language impairment in a case of a complex Chromosomal Rearrangement with a breakpoint downstream of foxp2
Molecular Cytogenetics, 2015Co-Authors: Daniela Moralli, Ron Nudel, May T M Chan, Catherine M Green, Emanuela V Volpi, Antonio Benitezburraco, Dianne F Newbury, Paloma GarciabellidoAbstract:Background: We report on a young female, who presents with a severe speech and language disorder and a balanced de novo complex Chromosomal Rearrangement, likely to have resulted from a chromosome 7 pericentromeric inversion, followed by a chromosome 7 and 11 translocation. Results: Using molecular cytogenetics, we mapped the four breakpoints to 7p21.1-15.3 (chromosome position: 20,954,043-21,001,537, hg19), 7q31 (chromosome position: 114,528,369-114,556,605, hg19), 7q21.3 (chromosome position: 93,884,065-93,933,453, hg19) and 11p12 (chromosome position: 38,601,145-38,621,572, hg19). These regions contain only non-coding transcripts (ENSG00000232790 on 7p21.1 and TCONS_00013886, TCONS_00013887, TCONS_00014353, TCONS_00013888 on 7q21) indicating that no coding sequences are directly disrupted. The breakpoint on 7q31 mapped 200 kb downstream of FOXP2, a well-known language gene. No splice site or non-synonymous coding variants were found in the FOXP2 coding sequence. We were unable to detect any changes in the expression level of FOXP2 in fibroblast cells derived from the proband, although this may be the result of the low expression level of FOXP2 in these cells. Conclusions: We conclude that the phenotype observed in this patient either arises from a subtle change in FOXP2 regulation due to the disruption of a downstream element controlling its expression, or from the direct disruption of non-coding RNAs.
Emanuela V Volpi - One of the best experts on this subject based on the ideXlab platform.
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language impairment in a case of a complex Chromosomal Rearrangement with a breakpoint downstream of foxp2
Molecular Cytogenetics, 2015Co-Authors: Daniela Moralli, Ron Nudel, May T M Chan, Catherine M Green, Emanuela V Volpi, Antonio Benitezburraco, Dianne F Newbury, Paloma GarciabellidoAbstract:Background We report on a young female, who presents with a severe speech and language disorder and a balanced de novo complex Chromosomal Rearrangement, likely to have resulted from a chromosome 7 pericentromeric inversion, followed by a chromosome 7 and 11 translocation.
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language impairment in a case of a complex Chromosomal Rearrangement with a breakpoint downstream of foxp2
Molecular Cytogenetics, 2015Co-Authors: Daniela Moralli, Ron Nudel, May T M Chan, Catherine M Green, Emanuela V Volpi, Antonio Benitezburraco, Dianne F Newbury, Paloma GarciabellidoAbstract:Background: We report on a young female, who presents with a severe speech and language disorder and a balanced de novo complex Chromosomal Rearrangement, likely to have resulted from a chromosome 7 pericentromeric inversion, followed by a chromosome 7 and 11 translocation. Results: Using molecular cytogenetics, we mapped the four breakpoints to 7p21.1-15.3 (chromosome position: 20,954,043-21,001,537, hg19), 7q31 (chromosome position: 114,528,369-114,556,605, hg19), 7q21.3 (chromosome position: 93,884,065-93,933,453, hg19) and 11p12 (chromosome position: 38,601,145-38,621,572, hg19). These regions contain only non-coding transcripts (ENSG00000232790 on 7p21.1 and TCONS_00013886, TCONS_00013887, TCONS_00014353, TCONS_00013888 on 7q21) indicating that no coding sequences are directly disrupted. The breakpoint on 7q31 mapped 200 kb downstream of FOXP2, a well-known language gene. No splice site or non-synonymous coding variants were found in the FOXP2 coding sequence. We were unable to detect any changes in the expression level of FOXP2 in fibroblast cells derived from the proband, although this may be the result of the low expression level of FOXP2 in these cells. Conclusions: We conclude that the phenotype observed in this patient either arises from a subtle change in FOXP2 regulation due to the disruption of a downstream element controlling its expression, or from the direct disruption of non-coding RNAs.