Combining chromosome conformation capture and exome sequencing for simultaneous detection of structural and single-nucleotide variants.
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Gridina Maria, Lagunov Timofey, Belokopytova Polina, Torgunakov Nikita, Nuriddinov Miroslav, Nurislamov Artem, Nazarenko Lyudmila P, Kashevarova Anna A, Lopatkina Maria E, Vasilyev Stanislav, Zuev Andrey, Belyaeva Elena O, Salyukova Olga A, Cheremnykh Aleksandr D, Sukhanova Natalia N, Minzhenkova Marina E, Markova Zhanna G, Demina Nina A, Stepanchuk Yana, Khabarova Anna, Yan Alexandra, Valeev Emil, Koksharova Galina, Grigor'eva Elena V, Kokh Natalia, Lukjanova Tatiana, Maximova Yulia, Musatova Elizaveta, Shabanova Elena, Kechin Andrey, Khrapov Evgeniy, Boyarskih Uliana, Ryzhkova Oxana, Suntsova Maria, Matrosova Alina, Karoli Mikhail, Manakhov Andrey, Filipenko Maxim, Rogaev Evgeny, Shilova Nadezhda V, Lebedev Igor N, Fishman Veniamin
Аннотация
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.