Diagnostic yield of exome and genome sequencing after non-diagnostic multi-gene panels in patients with single-system diseases

Though next-generation sequencing (NGS) tests like exome sequencing (ES), genome sequencing (GS), and panels derived from exome and genome data (EGBP) are effective for rare diseases, the ideal diagnostic approach is debated. Limited research has explored reanalyzing raw ES and GS data post-negative...

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Published in:	Orphanet journal of rare diseases Vol. 19; no. 1; p. 216
Main Authors:	Wilke, Matheus V M B, Klee, Eric W, Dhamija, Radhika, Fervenza, Fernando C, Thomas, Brittany, Leung, Nelson, Hogan, Marie C, Hager, Megan M, Kolbert, Kayla J, Kemppainen, Jennifer L, Loftus, Elle C, Leitzen, Katie M, Vitek, Carolyn R, McAllister, Tammy, Lazaridis, Konstantinos N, Pinto E Vairo, Filippo
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 24-05-2024 BMC
Subjects:	Adolescent Adult Aged Analysis Diagnosis Diagnostic yield DNA sequencing Exome Exome - genetics Exome Sequencing - methods Female Gene panels Genetic screening Genetic testing Genome Health aspects High-Throughput Nucleotide Sequencing - methods Humans Male Methods Middle Aged Nucleotide sequencing Rare diseases Rare Diseases - diagnosis Rare Diseases - genetics Whole Genome Sequencing - methods Young Adult United States Exome Rare diseases Diagnostic yield Genetic testing Gene panels Genome
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Summary:	Though next-generation sequencing (NGS) tests like exome sequencing (ES), genome sequencing (GS), and panels derived from exome and genome data (EGBP) are effective for rare diseases, the ideal diagnostic approach is debated. Limited research has explored reanalyzing raw ES and GS data post-negative EGBP results for diagnostics. We analyzed complete ES/GS raw sequencing data from Mayo Clinic's Program for Rare and Undiagnosed Diseases (PRaUD) patients to assess whether supplementary findings could augment diagnostic yield. ES data from 80 patients (59 adults) and GS data from 20 patients (10 adults), averaging 43 years in age, were analyzed. Most patients had renal (n=44) and auto-inflammatory (n=29) phenotypes. Ninety-six cases had negative findings and in four cases additional genetic variants were found, including a variant related to a recently described disease (RRAGD-related hypomagnesemia), a variant missed due to discordant inheritance pattern (COL4A3), a variant with high allelic frequency (NPHS2) in the general population, and a variant associated with an initially untargeted phenotype (HNF1A). ES and GS show diagnostic yields comparable to EGBP for single-system diseases. However, EGBP's limitations in detecting new disease-associated genes underscore the necessity for periodic updates.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1750-1172 1750-1172
DOI:	10.1186/s13023-024-03213-x