المؤلفون: Yilmaz, Feyza, Gurusamy, Umamaheswaran, Mosley, Trenell J, Hallast, Pille, Kim, Kwondo, Mostovoy, Yulia, Purcell, Ryan H, Shaikh, Tamim H, Zwick, Michael E, Kwok, Pui-Yan, Lee, Charles, Mulle, Jennifer G

المصدر: Genome Medicine. 15(1)

مصطلحات موضوعية: Biological Sciences, Genetics, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Humans, Segmental Duplications, Genomic, Chromosome Mapping, Genomics, Syndrome, Haplotypes, DNA Copy Number Variations, 3q29, Structural variations, Genomic disorders, Schizophrenia, NAHR, Copy number variant(s), Clinical Sciences

الوصف: BackgroundHigh sequence identity between segmental duplications (SDs) can facilitate copy number variants (CNVs) via non-allelic homologous recombination (NAHR). These CNVs are one of the fundamental causes of genomic disorders such as the 3q29 deletion syndrome (del3q29S). There are 21 protein-coding genes lost or gained as a result of such recurrent 1.6-Mbp deletions or duplications, respectively, in the 3q29 locus. While NAHR plays a role in CNV occurrence, the factors that increase the risk of NAHR at this particular locus are not well understood.MethodsWe employed an optical genome mapping technique to characterize the 3q29 locus in 161 unaffected individuals, 16 probands with del3q29S and their parents, and 2 probands with the 3q29 duplication syndrome (dup3q29S). Long-read sequencing-based haplotype resolved de novo assemblies from 44 unaffected individuals, and 1 trio was used for orthogonal validation of haplotypes and deletion breakpoints.ResultsIn total, we discovered 34 haplotypes, of which 19 were novel haplotypes. Among these 19 novel haplotypes, 18 were detected in unaffected individuals, while 1 novel haplotype was detected on the parent-of-origin chromosome of a proband with the del3q29S. Phased assemblies from 44 unaffected individuals enabled the orthogonal validation of 20 haplotypes. In 89% (16/18) of the probands, breakpoints were confined to paralogous copies of a 20-kbp segment within the 3q29 SDs. In one del3q29S proband, the breakpoint was confined to a 374-bp region using long-read sequencing. Furthermore, we categorized del3q29S cases into three classes and dup3q29S cases into two classes based on breakpoints. Finally, we found no evidence of inversions in parent-of-origin chromosomes.ConclusionsWe have generated the most comprehensive haplotype map for the 3q29 locus using unaffected individuals, probands with del3q29S or dup3q29S, and available parents, and also determined the deletion breakpoint to be within a 374-bp region in one proband with del3q29S. These results should provide a better understanding of the underlying genetic architecture that contributes to the etiology of del3q29S and dup3q29S.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/6cv3233cTest

المؤلفون: Variants, Commission on Novel Technologies for Neurodevelopmental Copy Number, Buttermore, Elizabeth, Chamberlain, Stormy, Cody, Jannine, Costain, Gregory, Dang, Louis, DeWoody, Andrew, DeWoody, Yssa, Dies, Kira, Eichler, Evan, Girirajan, Santhosh, Gramm, Marie, Halladay, Alycia, Lal, Dennis, Lalli, Matthew, Levy, Tess, Logsdon, Glennis, Lowenstein, Daniel, Mefford, Heather, Mulle, Jennifer, Muotri, Alysson, Murphy, Melissa, Palma, Eduardo Perez, Pinter, Stefan, Pollak, Rebecca, Purcell, Ryan, Samaco, Rodney, Shah, Bina, Singh, Karun, So, Joyce, Sundberg, Maria, Veeraragavan, Surabi, Vogel-Farley, Vanessa, Wynshaw-Boris, Anthony

المصدر: American Journal of Human Genetics. 109(8)

مصطلحات موضوعية: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Human Genome, Intellectual and Developmental Disabilities (IDD), Neurosciences, Brain Disorders, DNA Copy Number Variations, Genome, Humans, Neurodevelopmental Disorders, Patient Advocacy, Phenotype, Commission on Novel Technologies for Neurodevelopmental Copy Number Variants, CNVs, biobank, community engagement, copy-number variants, genomic disorders, iPSCs, inclusion, infrastructure, long-read sequencing, neurodevelopment, neurological, patient centered, patient led, structural variants, systematic phenotyping, team science, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences

الوصف: Copy-number variants and structural variants (CNVs/SVs) drive many neurodevelopmental-related disorders. While many neurodevelopmental-related CNVs/SVs give rise to complex phenotypes, the overlap in phenotypic presentation between independent CNVs can be extensive and provides a motivation for shared approaches. This confluence at the level of clinical phenotype implies convergence in at least some aspects of the underlying genomic mechanisms. With this perspective, our Commission on Novel Technologies for Neurodevelopmental CNVs asserts that the time has arrived to approach neurodevelopmental-related CNVs/SVs as a class of disorders that can be identified, investigated, and treated on the basis of shared mechanisms and/or pathways (e.g., molecular, neurological, or developmental). To identify common etiologic mechanisms among uncommon neurodevelopmental-related disorders and to potentially identify common therapies, it is paramount for teams of scientists, clinicians, and patients to unite their efforts. We bring forward novel, collaborative, and integrative strategies to translational CNV/SV research that engages diverse stakeholders to help expedite therapeutic outcomes. We articulate a clear vision for piloted roadmap strategies to reduce patient/caregiver burden and redundancies, increase efficiency, avoid siloed data, and accelerate translational discovery across CNV/SV-based syndromes.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/3tc3h13fTest

المؤلفون: Chiara Auwerx, Maarja Jõeloo, Marie C. Sadler, Nicolò Tesio, Sven Ojavee, Charlie J. Clark, Reedik Mägi, Alexandre Reymond, Zoltán Kutalik

مصطلحات موضوعية: Genetics, Structural variation, CNV, GWAS, Time-to-event analysis, Common diseases, Pleiotropy, 16p13.11, 16p11.2, Genomic disorders

الوصف: Additional file 1: Supplemental Notes. Note S1. Microarray-based CNV calling. Note S2. Sample filtering criteria. Note S3. Probe and covariate selection for main GWAS analysis. Note S4. Post-CNV-GWAS summary statistics processing. Note S5. Estonian Biobank replication. Note S6. Subgrouping of CNV carriers. Note S7. BRCA1 deletion association with ovarian and other female cancers. Note S8. LDLR deletion association with ischemic heart disease. Note S9. 16p12.2 deletion associations. Note S10. 22q11.2 CNV associations.

العلاقة: https://figshare.com/articles/journal_contribution/Additional_file_1_of_Rare_copy-number_variants_as_modulators_of_common_disease_susceptibility/24955993Test

الإتاحة: https://doi.org/10.6084/m9.figshare.24955993.v1Test
https://figshare.com/articles/journal_contribution/Additional_file_1_of_Rare_copy-number_variants_as_modulators_of_common_disease_susceptibility/24955993Test

المؤلفون: Feyza Yilmaz, Umamaheswaran Gurusamy, Trenell J. Mosley, Pille Hallast, Kwondo Kim, Yulia Mostovoy, Ryan H. Purcell, Tamim H. Shaikh, Michael E. Zwick, Pui-Yan Kwok, Charles Lee, Jennifer G. Mulle

المصدر: Genome Medicine, Vol 15, Iss 1, Pp 1-17 (2023)

مصطلحات موضوعية: 3q29, Structural variations, Genomic disorders, Schizophrenia, NAHR, Copy number variant(s), Medicine, Genetics, QH426-470

الوصف: Abstract Background High sequence identity between segmental duplications (SDs) can facilitate copy number variants (CNVs) via non-allelic homologous recombination (NAHR). These CNVs are one of the fundamental causes of genomic disorders such as the 3q29 deletion syndrome (del3q29S). There are 21 protein-coding genes lost or gained as a result of such recurrent 1.6-Mbp deletions or duplications, respectively, in the 3q29 locus. While NAHR plays a role in CNV occurrence, the factors that increase the risk of NAHR at this particular locus are not well understood. Methods We employed an optical genome mapping technique to characterize the 3q29 locus in 161 unaffected individuals, 16 probands with del3q29S and their parents, and 2 probands with the 3q29 duplication syndrome (dup3q29S). Long-read sequencing-based haplotype resolved de novo assemblies from 44 unaffected individuals, and 1 trio was used for orthogonal validation of haplotypes and deletion breakpoints. Results In total, we discovered 34 haplotypes, of which 19 were novel haplotypes. Among these 19 novel haplotypes, 18 were detected in unaffected individuals, while 1 novel haplotype was detected on the parent-of-origin chromosome of a proband with the del3q29S. Phased assemblies from 44 unaffected individuals enabled the orthogonal validation of 20 haplotypes. In 89% (16/18) of the probands, breakpoints were confined to paralogous copies of a 20-kbp segment within the 3q29 SDs. In one del3q29S proband, the breakpoint was confined to a 374-bp region using long-read sequencing. Furthermore, we categorized del3q29S cases into three classes and dup3q29S cases into two classes based on breakpoints. Finally, we found no evidence of inversions in parent-of-origin chromosomes. Conclusions We have generated the most comprehensive haplotype map for the 3q29 locus using unaffected individuals, probands with del3q29S or dup3q29S, and available parents, and also determined the deletion breakpoint to be within a 374-bp region in one proband with del3q29S. These results should provide a better understanding of the underlying genetic architecture that contributes to the etiology of del3q29S and dup3q29S.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1756-994XTest

الوصول الحر: https://doaj.org/article/e1441505fb324218b0dd9286ccd86457Test

المؤلفون: Lisanne Vervoort, Joris R. Vermeesch

المصدر: Exploration of Medicine, Vol 4, Iss 2, Pp 166-175 (2023)

مصطلحات موضوعية: genomic disorders, low copy repeats, segmental duplications, Other systems of medicine, RZ201-999

الوصف: DNA paralogs that have a length of at least 1 kilobase (kb) and are duplicated with a sequence identity of over 90% are classified as low copy repeats (LCRs) or segmental duplications (SDs). They constitute 6.6% of the genome and are clustering in specific genomic loci. Due to the high sequence homology between these duplicated regions, they can misalign during meiosis resulting in non-allelic homologous recombination (NAHR) and leading to structural variation such as deletions, duplications, inversions, and translocations. When such rearrangements result in a clinical phenotype, they are categorized as a genomic disorder. The presence of multiple copies of larger genomic segments offers opportunities for evolution. First, the creation of new genes in the human lineage will lead to human-specific traits and adaptation. Second, LCR variation between human populations can give rise to phenotypic variability. Hence, the rearrangement predisposition associated with LCRs should be interpreted in the context of the evolutionary advantages.

وصف الملف: electronic resource

العلاقة: https://www.explorationpub.com/Journals/em/Article/1001131Test; https://doaj.org/toc/2692-3106Test

الوصول الحر: https://doaj.org/article/48aec05f6eab491582baa9901191bdd9Test

المؤلفون: Gang Peng, Qinghua Zhou, Hongyan Chai, Jiadi Wen, Hongyu Zhao, Hugh S. Taylor, Yong‐Hui Jiang, Peining Li

المصدر: Molecular Genetics & Genomic Medicine, Vol 11, Iss 8, Pp n/a-n/a (2023)

مصطلحات موضوعية: chromosome microarray analysis (CMA), genomic disorders, pathogenic copy number variants (pCNVs), pregnancy loss (PL), products of conception (POC), spontaneous abortion (SAB), Genetics, QH426-470

الوصف: Abstract A meta‐analysis on seven large case series (>1000 cases) of chromosome microarray analysis (CMA) on products of conceptions (POC) evaluated the diagnostic yields of genomic disorders and syndromic pathogenic copy number variants (pCNVs) from a collection of 35,130 POC cases. CMA detected chromosomal abnormalities and pCNVs in approximately 50% and 2.5% of cases, respectively. The genomic disorders and syndromic pCNVs accounted for 31% of the detected pCNVs, and their incidences in POC ranged from 1/750 to 1/12,000. The newborn incidences of these genomic disorders and syndromic pCNVs were estimated in a range of 1/4000 to 1/50,000 live births from population genetic studies and diagnostic yields of a large case series of 32,587 pediatric patients. The risk of spontaneous abortion (SAB) for DiGeorge syndrome (DGS), Wolf–Hirschhorn syndrome (WHS), and William–Beuren syndrome (WBS) was 42%, 33%, and 21%, respectively. The estimated overall risk of SAB for major genomic disorders and syndromic pCNVs was approximately 38%, which was significantly lower than the 94% overall risk of SAB for chromosomal abnormalities. Further classification on levels of risk of SAB to high (>75%), intermediate (51%–75%), and low (26%–50%) for known chromosomal abnormalities, genomic disorders, and syndromic pCNVs could provide evidence‐based interpretation in prenatal diagnosis and genetic counseling.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2324-9269Test

الوصول الحر: https://doaj.org/article/b6114eb278a54495b6af068716582854Test

المؤلفون: Mostovoy, Yulia, Yilmaz, Feyza, Chow, Stephen K, Chu, Catherine, Lin, Chin, Geiger, Elizabeth A, Meeks, Naomi JL, Chatfield, Kathryn C, Coughlin, Curtis R, Surti, Urvashi, Kwok, Pui-Yan, Shaikh, Tamim H

المصدر: Genetics. 217(2)

مصطلحات موضوعية: Biological Sciences, Genetics, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Chromosome Breakpoints, Chromosome Deletion, Chromosome Disorders, Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 16, Craniofacial Abnormalities, Developmental Disabilities, Genomic Structural Variation, Heart Defects, Congenital, Humans, Intellectual Disability, Mental Disorders, Segmental Duplications, Genomic, Seizures, Williams Syndrome, segmental duplications, genome mapping, structural variation, genomic disorders, Developmental Biology, Biochemistry and cell biology

الوصف: Segmental duplications (SDs) are a class of long, repetitive DNA elements whose paralogs share a high level of sequence similarity with each other. SDs mediate chromosomal rearrangements that lead to structural variation in the general population as well as genomic disorders associated with multiple congenital anomalies, including the 7q11.23 (Williams-Beuren Syndrome, WBS), 15q13.3, and 16p12.2 microdeletion syndromes. Population-level characterization of SDs has generally been lacking because most techniques used for analyzing these complex regions are both labor and cost intensive. In this study, we have used a high-throughput technique to genotype complex structural variation with a single molecule, long-range optical mapping approach. We characterized SDs and identified novel structural variants (SVs) at 7q11.23, 15q13.3, and 16p12.2 using optical mapping data from 154 phenotypically normal individuals from 26 populations comprising five super-populations. We detected several novel SVs for each locus, some of which had significantly different prevalence between populations. Additionally, we localized the microdeletion breakpoints to specific paralogous duplicons located within complex SDs in two patients with WBS, one patient with 15q13.3, and one patient with 16p12.2 microdeletion syndromes. The population-level data presented here highlights the extreme diversity of large and complex SVs within SD-containing regions. The approach we outline will greatly facilitate the investigation of the role of inter-SD structural variation as a driver of chromosomal rearrangements and genomic disorders.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/15562671Test

المؤلفون: Alyssa S. Wetzel, Benjamin W. Darbro

المصدر: BMC Genomic Data, Vol 23, Iss 1, Pp 1-3 (2022)

مصطلحات موضوعية: Copy number variant, Microdeletion, Microduplication, Microduplication/microdeletion disorders, Genomic disorders, Genetics, QH426-470

الوصف: Abstract Objective The phenotypic spectrum of human microdeletion and microduplication syndromes (MMS) is heterogeneous but often involves intellectual disability, autism spectrum disorders, dysmorphic features and/or multiple congenital anomalies. While the common recurrent copy number variants (CNVs) which underlie these MMS have been well-studied, the expansion of clinical genomic testing has led to the identification of many rare non-recurrent MMS. To date, hundreds of unique MMS have been reported in the medical literature, and no single resource exists which compiles all these MMS in one location. This comprehensive list of MMS will aid further study of CNV disorders as well as serve as a resource for clinical laboratories performing diagnostic CNV testing. Data description Here we provide a comprehensive list of MMS which have been reported in the medical literature to date. This list is sorted by genomic location, and for each MMS, we provide a list of publications for referral, as well as the consensus coordinates, representative region, shortest regions of overlap (SRO), and/or subregions where applicable.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2730-6844Test

الوصول الحر: https://doaj.org/article/11d5a9290fc4459481bcf3b716e9e31cTest

المؤلفون: Peng, Gang, Zhou, Qinghua, Chai, Hongyan, Wen, Jiadi, Zhao, Hongyu, Taylor, Hugh S., Jiang, Yong-Hui, Li, Peining

المساهمون: Medical and Molecular Genetics, School of Medicine

المصدر: PMC

مصطلحات موضوعية: Chromosome microarray analysis (CMA), Genomic disorders, Pathogenic copy number variants (pCNVs), Pregnancy loss (PL), Products of conception (POC), Spontaneous abortion (SAB)

الوصف: A meta-analysis on seven large case series (>1000 cases) of chromosome microarray analysis (CMA) on products of conceptions (POC) evaluated the diagnostic yields of genomic disorders and syndromic pathogenic copy number variants (pCNVs) from a collection of 35,130 POC cases. CMA detected chromosomal abnormalities and pCNVs in approximately 50% and 2.5% of cases, respectively. The genomic disorders and syndromic pCNVs accounted for 31% of the detected pCNVs, and their incidences in POC ranged from 1/750 to 1/12,000. The newborn incidences of these genomic disorders and syndromic pCNVs were estimated in a range of 1/4000 to 1/50,000 live births from population genetic studies and diagnostic yields of a large case series of 32,587 pediatric patients. The risk of spontaneous abortion (SAB) for DiGeorge syndrome (DGS), Wolf-Hirschhorn syndrome (WHS), and William-Beuren syndrome (WBS) was 42%, 33%, and 21%, respectively. The estimated overall risk of SAB for major genomic disorders and syndromic pCNVs was approximately 38%, which was significantly lower than the 94% overall risk of SAB for chromosomal abnormalities. Further classification on levels of risk of SAB to high (>75%), intermediate (51%-75%), and low (26%-50%) for known chromosomal abnormalities, genomic disorders, and syndromic pCNVs could provide evidence-based interpretation in prenatal diagnosis and genetic counseling.

وصف الملف: application/pdf

العلاقة: Molecular Genetics & Genomic Medicine; Peng G, Zhou Q, Chai H, et al. Estimation on risk of spontaneous abortions by genomic disorders from a meta-analysis of microarray results on large case series of pregnancy losses. Mol Genet Genomic Med. 2023;11(8):e2181. doi:10.1002/mgg3.2181; https://hdl.handle.net/1805/38602Test

الإتاحة: https://doi.org/10.1002/mgg3.2181Test
https://hdl.handle.net/1805/38602Test

المؤلفون: Katalin Komlósi, Attila Gyenesei, Judit Bene

المصدر: Frontiers in Genetics, Vol 13 (2022)

مصطلحات موضوعية: copy number variation (CNV), rare disorders, genomic disorders, Mendelian disease, genomic rearrangement, Genetics, QH426-470

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fgene.2022.898059/fullTest; https://doaj.org/toc/1664-8021Test

الوصول الحر: https://doaj.org/article/049ecdf2784c4eaf8ad4ae33d1b8b719Test