Genome sequencing as a generic diagnostic strategy for rare disease

• DOI: 10.1186/s13073-024-01301-y
• Publication Date: 2024-02-14T15:03:33Z
• Authors: Gaby Schobers; Ronny Derks; Amber den Ouden; Hilde Swinkels; Jeroen van Reeuwijk; Ermanno Bosgoed; Dorien Lugtenberg; Su Ming Sun; Jordi Corominas G...; Marjan Weiss; Marinus J. Blok; Richelle A. C. M....; Tom Hofste; Debby Hellebrekers; Nicole de Leeuw; Alexander Stegmann; Erik-Jan Kamsteeg; Aimee D. C. Paulu...; Marjolijn J. L. L...; Xiangqun Zheng Br...; John Peden; Alejandra Gutierrez; Adam Pullen; Tom Payne; Christian Gilissen; Arthur van den Wi...; Han G. Brunner; Marcel Nelen; Helger G. Yntema; Lisenka E. L. M. ...
• Keywords: Indel

Abstract Background To diagnose the full spectrum of hereditary and congenital diseases, genetic laboratories use many different workflows, ranging from karyotyping to exome sequencing. A single generic high-throughput workflow would greatly increase efficiency. We assessed whether genome sequencing (GS) can replace these existing workflows aimed at germline diagnosis for rare disease. Methods performed short-read GS (NovaSeq™6000; 150 bp paired-end reads, 37 × mean coverage) on 1000 cases with 1271 known clinically relevant variants, identified across representative our tertiary diagnostic centers. Variants were categorized into small variants (single nucleotide indels < 50 bp), large (copy number short tandem repeats) other (structural aneuploidies). Variant calling format files queried per variant, which workflow-specific true positive rates (TPRs) detection determined. TPR ≥ 98% was considered threshold transition GS. GS-first scenario generated laboratory, using efficacy predicted false negative as primary outcome measures. As input, we modeled path all 24,570 individuals referred in 2022, combining clinical referral, underlying workflow(s) GS, variant type(s) be detected. Results Overall, 95% (1206/1271) Detection differed category: 96% (826/860), 93% (341/366), 87% (39/45). TPRs varied between (79–100%), 7/10 being replaceable by Models laboratory indicate that a strategy feasible 84.9% referrals (750/883), translating 71% (17,444/24,570) receiving their test. An estimated rate 0.3% could expected. Conclusions capture ‘GS-first strategy’ majority indications genetics lab.