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
Institute of Cytology and Genetics, 10, Prospekt Akademika Lavrent'yeva, Novosibirsk, 630090, Russia.
Novosibirsk State University, 1, Pirogova Str, Novosibirsk, 630090, Russia.
Genome Med. 2025 May 7;17(1):47. doi: 10.1186/s13073-025-01471-3.
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).
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.
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.
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.
先天性疾病的有效分子诊断取决于全面的基因组分析，传统上依赖于针对每种变异类型的各种方法——针对单核苷酸变异（SNV）的全外显子组或基因组测序、针对拷贝数变异（CNV）的阵列比较基因组杂交以及针对结构变异（SV）的显微镜检查。
我们引入了一种将外显子组测序与染色体构象捕获相结合的新型综合方法，称为Exo-C。该方法能够同时鉴定临床相关基因中的SNV和全基因组中的SV，并允许分析杂合和嵌合携带者。通过靶向长读长测序增强后，Exo-C演变成一种具有成本效益的解决方案，能够以碱基对精度解析复杂的SV。
将Exo-C应用于66个人类样本，在检测染色体易位和SNV方面实现了100%的召回率和73%的精度。我们进一步对其在倒位和CNV方面的性能进行了基准测试，并证明了其在检测嵌合SV和解决诊断挑战性病例方面的效用。
通过几个案例研究，我们展示了Exo-C的多方面应用如何能够有效地发现各种致病变异，并阐明罕见疾病患者的疾病机制。
