Interchromosomal template-switching as a novel molecular mechanism for imprinting perturbations associated with Temple syndrome
Abstract Background Intrachromosomal triplications (TRP) can contribute to disease etiology via gene dosage effects, gene disruption, position effects, or fusion gene formation. Recently, post-zygotic de novo triplications adjacent to copy-number neutral genomic intervals with runs of homozygosity (...
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| Format: | Article |
| Language: | English |
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BMC
2019-04-01
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| Series: | Genome Medicine |
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| Online Access: | http://link.springer.com/article/10.1186/s13073-019-0633-y |
| _version_ | 1828870059832901632 |
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| author | Claudia M. B. Carvalho Zeynep Coban-Akdemir Hadia Hijazi Bo Yuan Matthew Pendleton Eoghan Harrington John Beaulaurier Sissel Juul Daniel J. Turner Rupa S. Kanchi Shalini N. Jhangiani Donna M. Muzny Richard A. Gibbs Baylor-Hopkins Center for Mendelian Genomics Pawel Stankiewicz John W. Belmont Chad A. Shaw Sau Wai Cheung Neil A. Hanchard V. Reid Sutton Patricia I. Bader James R. Lupski |
| author_facet | Claudia M. B. Carvalho Zeynep Coban-Akdemir Hadia Hijazi Bo Yuan Matthew Pendleton Eoghan Harrington John Beaulaurier Sissel Juul Daniel J. Turner Rupa S. Kanchi Shalini N. Jhangiani Donna M. Muzny Richard A. Gibbs Baylor-Hopkins Center for Mendelian Genomics Pawel Stankiewicz John W. Belmont Chad A. Shaw Sau Wai Cheung Neil A. Hanchard V. Reid Sutton Patricia I. Bader James R. Lupski |
| author_sort | Claudia M. B. Carvalho |
| collection | DOAJ |
| description | Abstract Background Intrachromosomal triplications (TRP) can contribute to disease etiology via gene dosage effects, gene disruption, position effects, or fusion gene formation. Recently, post-zygotic de novo triplications adjacent to copy-number neutral genomic intervals with runs of homozygosity (ROH) have been shown to result in uniparental isodisomy (UPD). The genomic structure of these complex genomic rearrangements (CGRs) shows a consistent pattern of an inverted triplication flanked by duplications (DUP-TRP/INV-DUP) formed by an iterative DNA replisome template-switching mechanism during replicative repair of a single-ended, double-stranded DNA (seDNA), the ROH results from an interhomolog or nonsister chromatid template switch. It has been postulated that these CGRs may lead to genetic abnormalities in carriers due to dosage-sensitive genes mapping within the copy-number variant regions, homozygosity for alleles at a locus causing an autosomal recessive (AR) disease trait within the ROH region, or imprinting-associated diseases. Methods Here, we report a family wherein the affected subject carries a de novo 2.2-Mb TRP followed by 42.2 Mb of ROH and manifests clinical features overlapping with those observed in association with chromosome 14 maternal UPD (UPD(14)mat). UPD(14)mat can cause clinical phenotypic features enabling a diagnosis of Temple syndrome. This CGR was then molecularly characterized by high-density custom aCGH, genome-wide single-nucleotide polymorphism (SNP) and methylation arrays, exome sequencing (ES), and the Oxford Nanopore long-read sequencing technology. Results We confirmed the postulated DUP-TRP/INV-DUP structure by multiple orthogonal genomic technologies in the proband. The methylation status of known differentially methylated regions (DMRs) on chromosome 14 revealed that the subject shows the typical methylation pattern of UPD(14)mat. Consistent with these molecular findings, the clinical features overlap with those observed in Temple syndrome, including speech delay. Conclusions These data provide experimental evidence that, in humans, triplication can lead to segmental UPD and imprinting disease. Importantly, genotype/phenotype analyses further reveal how a post-zygotically generated complex structural variant, resulting from a replication-based mutational mechanism, contributes to expanding the clinical phenotype of known genetic syndromes. Mechanistically, such events can distort transmission genetics resulting in homozygosity at a locus for which only one parent is a carrier as well as cause imprinting diseases. |
| first_indexed | 2024-12-13T06:03:14Z |
| format | Article |
| id | doaj.art-9879805980e143e1af4e72fdff58ff03 |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-12-13T06:03:14Z |
| publishDate | 2019-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-9879805980e143e1af4e72fdff58ff032022-12-21T23:57:17ZengBMCGenome Medicine1756-994X2019-04-0111111410.1186/s13073-019-0633-yInterchromosomal template-switching as a novel molecular mechanism for imprinting perturbations associated with Temple syndromeClaudia M. B. Carvalho0Zeynep Coban-Akdemir1Hadia Hijazi2Bo Yuan3Matthew Pendleton4Eoghan Harrington5John Beaulaurier6Sissel Juul7Daniel J. Turner8Rupa S. Kanchi9Shalini N. Jhangiani10Donna M. Muzny11Richard A. Gibbs12Baylor-Hopkins Center for Mendelian GenomicsPawel Stankiewicz13John W. Belmont14Chad A. Shaw15Sau Wai Cheung16Neil A. Hanchard17V. Reid Sutton18Patricia I. Bader19James R. Lupski20Department of Molecular and Human Genetics, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineOxford Nanopore Technologies IncOxford Nanopore Technologies IncOxford Nanopore Technologies IncOxford Nanopore Technologies IncOxford Nanopore Technologies LtdUT MD Anderson Cancer CenterHuman Genome Sequencing Center, Baylor College of MedicineHuman Genome Sequencing Center, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineCarle ClinicDepartment of Molecular and Human Genetics, Baylor College of MedicineAbstract Background Intrachromosomal triplications (TRP) can contribute to disease etiology via gene dosage effects, gene disruption, position effects, or fusion gene formation. Recently, post-zygotic de novo triplications adjacent to copy-number neutral genomic intervals with runs of homozygosity (ROH) have been shown to result in uniparental isodisomy (UPD). The genomic structure of these complex genomic rearrangements (CGRs) shows a consistent pattern of an inverted triplication flanked by duplications (DUP-TRP/INV-DUP) formed by an iterative DNA replisome template-switching mechanism during replicative repair of a single-ended, double-stranded DNA (seDNA), the ROH results from an interhomolog or nonsister chromatid template switch. It has been postulated that these CGRs may lead to genetic abnormalities in carriers due to dosage-sensitive genes mapping within the copy-number variant regions, homozygosity for alleles at a locus causing an autosomal recessive (AR) disease trait within the ROH region, or imprinting-associated diseases. Methods Here, we report a family wherein the affected subject carries a de novo 2.2-Mb TRP followed by 42.2 Mb of ROH and manifests clinical features overlapping with those observed in association with chromosome 14 maternal UPD (UPD(14)mat). UPD(14)mat can cause clinical phenotypic features enabling a diagnosis of Temple syndrome. This CGR was then molecularly characterized by high-density custom aCGH, genome-wide single-nucleotide polymorphism (SNP) and methylation arrays, exome sequencing (ES), and the Oxford Nanopore long-read sequencing technology. Results We confirmed the postulated DUP-TRP/INV-DUP structure by multiple orthogonal genomic technologies in the proband. The methylation status of known differentially methylated regions (DMRs) on chromosome 14 revealed that the subject shows the typical methylation pattern of UPD(14)mat. Consistent with these molecular findings, the clinical features overlap with those observed in Temple syndrome, including speech delay. Conclusions These data provide experimental evidence that, in humans, triplication can lead to segmental UPD and imprinting disease. Importantly, genotype/phenotype analyses further reveal how a post-zygotically generated complex structural variant, resulting from a replication-based mutational mechanism, contributes to expanding the clinical phenotype of known genetic syndromes. Mechanistically, such events can distort transmission genetics resulting in homozygosity at a locus for which only one parent is a carrier as well as cause imprinting diseases.http://link.springer.com/article/10.1186/s13073-019-0633-yTriplicationDUP-TRP/INV-DUPComplex genomic rearrangementMMBIRReplicative-based mechanismInter-homologous chromosomal template switch |
| spellingShingle | Claudia M. B. Carvalho Zeynep Coban-Akdemir Hadia Hijazi Bo Yuan Matthew Pendleton Eoghan Harrington John Beaulaurier Sissel Juul Daniel J. Turner Rupa S. Kanchi Shalini N. Jhangiani Donna M. Muzny Richard A. Gibbs Baylor-Hopkins Center for Mendelian Genomics Pawel Stankiewicz John W. Belmont Chad A. Shaw Sau Wai Cheung Neil A. Hanchard V. Reid Sutton Patricia I. Bader James R. Lupski Interchromosomal template-switching as a novel molecular mechanism for imprinting perturbations associated with Temple syndrome Genome Medicine Triplication DUP-TRP/INV-DUP Complex genomic rearrangement MMBIR Replicative-based mechanism Inter-homologous chromosomal template switch |
| title | Interchromosomal template-switching as a novel molecular mechanism for imprinting perturbations associated with Temple syndrome |
| title_full | Interchromosomal template-switching as a novel molecular mechanism for imprinting perturbations associated with Temple syndrome |
| title_fullStr | Interchromosomal template-switching as a novel molecular mechanism for imprinting perturbations associated with Temple syndrome |
| title_full_unstemmed | Interchromosomal template-switching as a novel molecular mechanism for imprinting perturbations associated with Temple syndrome |
| title_short | Interchromosomal template-switching as a novel molecular mechanism for imprinting perturbations associated with Temple syndrome |
| title_sort | interchromosomal template switching as a novel molecular mechanism for imprinting perturbations associated with temple syndrome |
| topic | Triplication DUP-TRP/INV-DUP Complex genomic rearrangement MMBIR Replicative-based mechanism Inter-homologous chromosomal template switch |
| url | http://link.springer.com/article/10.1186/s13073-019-0633-y |
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