A novel approach for simultaneous detection of structural and single-nucleotide variants based on a combination of chromosome conformation capture and exome sequencing
Gridina M., Lagunov T., Belokopytova P., Torgunakov N., Nuriddinov M., Nurislamov A., Nazarenko L.P., Kashevarova A.A., Lopatkina M.E., Belyaeva E.O., Salykova O.A., Cheremnykh A.D., Sukhanova N.N., Minzhenkova M.E., Markova Zh.G., Demina N.A., Stepanchuk Y., Khabarova A., Yan A., Valeev E., Koksharova G., Grogor’eva E.V., Kokh N., Lukjanova T., Maximova Y., Musatova E., Shabanova E., Kechin A., Khrapov E., Boyarskih U., Ryzhkova O., Suntsova M., Matrosova A., Karoli M., Manakhov A., Filipenko M., Rogaev E., Shilova N.V., Lebedev I.N., Fishman V.S.
BMC Medical Genomics (this version posted January 29, 2024)
DOI: 10.1101/2024.01.26.577292
Effective molecular diagnosis of congenital diseases hinges on comprehensive 36 genomic analysis, traditionally reliant on various methodologies specific to each variant 37 type—whole exome or genome sequencing for single nucleotide variants (SNVs), array 38 CGH for copy-number variants (CNVs), and microscopy for structural variants (SVs). We 39 introduce a novel, integrative approach combining exome sequencing with chromosome 40 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 42 heterozygous and mosaic carriers. Enhanced with targeted long-read sequencing, Exo43 C evolves into a cost-efficient solution capable of resolving complex SVs at base-pair 44 accuracy. Through several case studies, we demonstrate how Exo-C's multifaceted 45 application can effectively uncover diverse causative variants and elucidate disease 46 mechanisms in patients with rare disorders.