A novel approach for simultaneous detection of structural and single-nucleotide variants based on a combination of chromosome conformation capture and exome sequencing

A novel approach for simultaneous detection of structural and single-nucleotide variants based on a combination of chromosome conformation capture and exome sequencing Abstract 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. 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. Competing Interest Statement The authors have declared no competing interest. Subject Area - Biochemistry (17728) - Bioengineering (13916) - Bioinformatics (42037) - Biophysics (21488) - Cancer Biology (18636) - Cell Biology (25552) - Clinical Trials (138) - Developmental Biology (13401) - Ecology (19940) - Epidemiology (2067) - Evolutionary Biology (24367) - Genetics (15621) - Genomics (22545) - Immunology (17764) - Microbiology (40475) - Molecular Biology (17208) - Neuroscience (88744) - Paleontology (667) - Pathology (2842) - Pharmacology and Toxicology (4834) - Physiology (7659) - Plant Biology (15175) - Synthetic Biology (4304) - Systems Biology (9834) - Zoology (2272)