Combining chromosome conformation capture and exome sequencing for simultaneous detection of structural and single-nucleotide variants
Abstract Background Effective molecular diagnosis of congenital diseases hinges on comprehensive genomic analysis, traditionally reliant on various methodologies specific to each variant type—whole exome or genome sequencing for single nucleotide variants (SNVs), array CGH for copy-number variants (...
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2025-05-01
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| Series: | Genome Medicine |
| Online Access: | https://doi.org/10.1186/s13073-025-01471-3 |
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| author | Maria Gridina Timofey Lagunov Polina Belokopytova Nikita Torgunakov Miroslav Nuriddinov Artem Nurislamov Lyudmila P. Nazarenko Anna A. Kashevarova Maria E. Lopatkina Stanislav Vasilyev Andrey Zuev Elena O. Belyaeva Olga A. Salyukova Aleksandr D. Cheremnykh Natalia N. Sukhanova Marina E. Minzhenkova Zhanna G. Markova Nina A. Demina Yana Stepanchuk Anna Khabarova Alexandra Yan Emil Valeev Galina Koksharova Elena V. Grigor’eva Natalia Kokh Tatiana Lukjanova Yulia Maximova Elizaveta Musatova Elena Shabanova Andrey Kechin Evgeniy Khrapov Uliana Boyarskih Oxana Ryzhkova Maria Suntsova Alina Matrosova Mikhail Karoli Andrey Manakhov Maxim Filipenko Evgeny Rogaev Nadezhda V. Shilova Igor N. Lebedev Veniamin Fishman |
| author_facet | Maria Gridina Timofey Lagunov Polina Belokopytova Nikita Torgunakov Miroslav Nuriddinov Artem Nurislamov Lyudmila P. Nazarenko Anna A. Kashevarova Maria E. Lopatkina Stanislav Vasilyev Andrey Zuev Elena O. Belyaeva Olga A. Salyukova Aleksandr D. Cheremnykh Natalia N. Sukhanova Marina E. Minzhenkova Zhanna G. Markova Nina A. Demina Yana Stepanchuk Anna Khabarova Alexandra Yan Emil Valeev Galina Koksharova Elena V. Grigor’eva Natalia Kokh Tatiana Lukjanova Yulia Maximova Elizaveta Musatova Elena Shabanova Andrey Kechin Evgeniy Khrapov Uliana Boyarskih Oxana Ryzhkova Maria Suntsova Alina Matrosova Mikhail Karoli Andrey Manakhov Maxim Filipenko Evgeny Rogaev Nadezhda V. Shilova Igor N. Lebedev Veniamin Fishman |
| author_sort | Maria Gridina |
| collection | DOAJ |
| description | Abstract Background Effective molecular diagnosis of congenital diseases hinges on comprehensive genomic analysis, traditionally reliant on various methodologies specific to each variant type—whole exome or genome sequencing for single nucleotide variants (SNVs), array CGH for copy-number variants (CNVs), and microscopy for structural variants (SVs). Methods We introduce a novel, integrative approach combining exome sequencing with chromosome conformation capture, termed Exo-C. This method enables the concurrent identification of SNVs in clinically relevant genes and SVs across the genome and allows analysis of heterozygous and mosaic carriers. Enhanced with targeted long-read sequencing, Exo-C evolves into a cost-efficient solution capable of resolving complex SVs at base-pair accuracy. Results Applied to 66 human samples Exo-C achieved 100% recall and 73% precision in detecting chromosomal translocations and SNVs. We further benchmarked its performance for inversions and CNVs and demonstrated its utility in detecting mosaic SVs and resolving diagnostically challenging cases. Conclusions Through several case studies, we demonstrate how Exo-C’s multifaceted application can effectively uncover diverse causative variants and elucidate disease mechanisms in patients with rare disorders. |
| format | Article |
| id | doaj-art-58a6060668ec40e3b08fbf9ee2808fef |
| institution | OA Journals |
| issn | 1756-994X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj-art-58a6060668ec40e3b08fbf9ee2808fef2025-08-20T01:49:36ZengBMCGenome Medicine1756-994X2025-05-0117112310.1186/s13073-025-01471-3Combining chromosome conformation capture and exome sequencing for simultaneous detection of structural and single-nucleotide variantsMaria Gridina0Timofey Lagunov1Polina Belokopytova2Nikita Torgunakov3Miroslav Nuriddinov4Artem Nurislamov5Lyudmila P. Nazarenko6Anna A. Kashevarova7Maria E. Lopatkina8Stanislav Vasilyev9Andrey Zuev10Elena O. Belyaeva11Olga A. Salyukova12Aleksandr D. Cheremnykh13Natalia N. Sukhanova14Marina E. Minzhenkova15Zhanna G. Markova16Nina A. Demina17Yana Stepanchuk18Anna Khabarova19Alexandra Yan20Emil Valeev21Galina Koksharova22Elena V. Grigor’eva23Natalia Kokh24Tatiana Lukjanova25Yulia Maximova26Elizaveta Musatova27Elena Shabanova28Andrey Kechin29Evgeniy Khrapov30Uliana Boyarskih31Oxana Ryzhkova32Maria Suntsova33Alina Matrosova34Mikhail Karoli35Andrey Manakhov36Maxim Filipenko37Evgeny Rogaev38Nadezhda V. Shilova39Igor N. Lebedev40Veniamin Fishman41Institute of Cytology and GeneticsInstitute of Cytology and GeneticsInstitute of Cytology and GeneticsInstitute of Cytology and GeneticsInstitute of Cytology and GeneticsInstitute of Cytology and GeneticsResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesResearch Centre for Medical GeneticsResearch Centre for Medical GeneticsResearch Centre for Medical GeneticsInstitute of Cytology and GeneticsInstitute of Cytology and GeneticsInstitute of Cytology and GeneticsInstitute of Cytology and GeneticsInstitute of Cytology and GeneticsInstitute of Cytology and GeneticsInstitute of Cytology and GeneticsCenter for Family Care and ReproductionCenter for Family Care and ReproductionGenetics and Reproductive Medicine Center, “GENETICO” PJSCNorth-Western State Medical University named after I.I. MechnikovNovosibirsk State UniversityInstitute of Chemical Biology and Fundamental MedicineInstitute of Chemical Biology and Fundamental MedicineResearch Centre for Medical GeneticsSechenov First Moscow State Medical UniversitySechenov First Moscow State Medical UniversitySirius University of Science and Technology, Sirius Federal TerritorySirius University of Science and Technology, Sirius Federal TerritoryInstitute of Chemical Biology and Fundamental MedicineSirius University of Science and Technology, Sirius Federal TerritoryResearch Centre for Medical GeneticsResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesInstitute of Cytology and GeneticsAbstract Background Effective molecular diagnosis of congenital diseases hinges on comprehensive genomic analysis, traditionally reliant on various methodologies specific to each variant type—whole exome or genome sequencing for single nucleotide variants (SNVs), array CGH for copy-number variants (CNVs), and microscopy for structural variants (SVs). Methods We introduce a novel, integrative approach combining exome sequencing with chromosome conformation capture, termed Exo-C. This method enables the concurrent identification of SNVs in clinically relevant genes and SVs across the genome and allows analysis of heterozygous and mosaic carriers. Enhanced with targeted long-read sequencing, Exo-C evolves into a cost-efficient solution capable of resolving complex SVs at base-pair accuracy. Results Applied to 66 human samples Exo-C achieved 100% recall and 73% precision in detecting chromosomal translocations and SNVs. We further benchmarked its performance for inversions and CNVs and demonstrated its utility in detecting mosaic SVs and resolving diagnostically challenging cases. Conclusions Through several case studies, we demonstrate how Exo-C’s multifaceted application can effectively uncover diverse causative variants and elucidate disease mechanisms in patients with rare disorders.https://doi.org/10.1186/s13073-025-01471-3 |
| spellingShingle | Maria Gridina Timofey Lagunov Polina Belokopytova Nikita Torgunakov Miroslav Nuriddinov Artem Nurislamov Lyudmila P. Nazarenko Anna A. Kashevarova Maria E. Lopatkina Stanislav Vasilyev Andrey Zuev Elena O. Belyaeva Olga A. Salyukova Aleksandr D. Cheremnykh Natalia N. Sukhanova Marina E. Minzhenkova Zhanna G. Markova Nina A. Demina Yana Stepanchuk Anna Khabarova Alexandra Yan Emil Valeev Galina Koksharova Elena V. Grigor’eva Natalia Kokh Tatiana Lukjanova Yulia Maximova Elizaveta Musatova Elena Shabanova Andrey Kechin Evgeniy Khrapov Uliana Boyarskih Oxana Ryzhkova Maria Suntsova Alina Matrosova Mikhail Karoli Andrey Manakhov Maxim Filipenko Evgeny Rogaev Nadezhda V. Shilova Igor N. Lebedev Veniamin Fishman Combining chromosome conformation capture and exome sequencing for simultaneous detection of structural and single-nucleotide variants Genome Medicine |
| title | Combining chromosome conformation capture and exome sequencing for simultaneous detection of structural and single-nucleotide variants |
| title_full | Combining chromosome conformation capture and exome sequencing for simultaneous detection of structural and single-nucleotide variants |
| title_fullStr | Combining chromosome conformation capture and exome sequencing for simultaneous detection of structural and single-nucleotide variants |
| title_full_unstemmed | Combining chromosome conformation capture and exome sequencing for simultaneous detection of structural and single-nucleotide variants |
| title_short | Combining chromosome conformation capture and exome sequencing for simultaneous detection of structural and single-nucleotide variants |
| title_sort | combining chromosome conformation capture and exome sequencing for simultaneous detection of structural and single nucleotide variants |
| url | https://doi.org/10.1186/s13073-025-01471-3 |
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