학술논문
Genome sequencing as a generic diagnostic strategy for rare disease
Document Type
Academic Journal
Author
Schobers, Gaby; Derks, Ronny; den Ouden, Amber; Swinkels, Hilde; van Reeuwijk, Jeroen; Bosgoed, Ermanno; Lugtenberg, Dorien; Sun, Su Ming; Corominas Galbany, Jordi; Weiss, Marjan; Blok, Marinus J.; Olde Keizer, Richelle A. C. M.; Hofste, Tom; Hellebrekers, Debby; de Leeuw, Nicole; Stegmann, Alexander; Kamsteeg, Erik-Jan; Paulussen, Aimee D. C.; Ligtenberg, Marjolijn J. L.; Bradley, Xiangqun Zheng; Peden, John; Gutierrez, Alejandra; Pullen, Adam; Payne, Tom; Gilissen, Christian; van den Wijngaard, Arthur; Brunner, Han G.; Nelen, Marcel; Yntema, Helger G.; Vissers, Lisenka E. L. M.
Source
Genome Medicine. February 14, 2024, Vol. 16 Issue 1
Subject
Language
English
ISSN
1756-994X
Abstract
Author(s): Gaby Schobers[sup.1,2], Ronny Derks[sup.1], Amber den Ouden[sup.1], Hilde Swinkels[sup.1], Jeroen van Reeuwijk[sup.1,2], Ermanno Bosgoed[sup.1], Dorien Lugtenberg[sup.1], Su Ming Sun[sup.3], Jordi Corominas Galbany[sup.1,2], Marjan Weiss[sup.1], Marinus J. Blok[sup.3], Richelle A. [...]
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 genetic diagnosis for rare disease. Methods We performed short-read GS (NovaSeq[TM]6000; 150 bp paired-end reads, 37 x mean coverage) on 1000 cases with 1271 known clinically relevant variants, identified across different workflows, representative of our tertiary diagnostic centers. Variants were categorized into small variants (single nucleotide variants and indels < 50 bp), large variants (copy number variants and short tandem repeats) and other variants (structural variants and aneuploidies). Variant calling format files were queried per variant, from which workflow-specific true positive rates (TPRs) for detection were determined. A TPR of [greater than or equal to] 98% was considered the threshold for transition to GS. A GS-first scenario was generated for our laboratory, using diagnostic efficacy and predicted false negative as primary outcome measures. As input, we modeled the diagnostic path for all 24,570 individuals referred in 2022, combining the clinical referral, the transition of the underlying workflow(s) to GS, and the variant type(s) to be detected. Results Overall, 95% (1206/1271) of variants were detected. Detection rates differed per variant category: small variants in 96% (826/860), large variants in 93% (341/366), and other variants in 87% (39/45). TPRs varied between workflows (79-100%), with 7/10 being replaceable by GS. Models for our laboratory indicate that a GS-first strategy would be feasible for 84.9% of clinical referrals (750/883), translating to 71% of all individuals (17,444/24,570) receiving GS as their primary test. An estimated false negative rate of 0.3% could be expected. Conclusions GS can capture clinically relevant germline variants in a 'GS-first strategy' for the majority of clinical indications in a genetics diagnostic lab. Keywords: Rare disease, Genome sequencing, Impact modeling, Reducing workflow complexity, Genetic diagnostic laboratories, Germline variant detection
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 genetic diagnosis for rare disease. Methods We performed short-read GS (NovaSeq[TM]6000; 150 bp paired-end reads, 37 x mean coverage) on 1000 cases with 1271 known clinically relevant variants, identified across different workflows, representative of our tertiary diagnostic centers. Variants were categorized into small variants (single nucleotide variants and indels < 50 bp), large variants (copy number variants and short tandem repeats) and other variants (structural variants and aneuploidies). Variant calling format files were queried per variant, from which workflow-specific true positive rates (TPRs) for detection were determined. A TPR of [greater than or equal to] 98% was considered the threshold for transition to GS. A GS-first scenario was generated for our laboratory, using diagnostic efficacy and predicted false negative as primary outcome measures. As input, we modeled the diagnostic path for all 24,570 individuals referred in 2022, combining the clinical referral, the transition of the underlying workflow(s) to GS, and the variant type(s) to be detected. Results Overall, 95% (1206/1271) of variants were detected. Detection rates differed per variant category: small variants in 96% (826/860), large variants in 93% (341/366), and other variants in 87% (39/45). TPRs varied between workflows (79-100%), with 7/10 being replaceable by GS. Models for our laboratory indicate that a GS-first strategy would be feasible for 84.9% of clinical referrals (750/883), translating to 71% of all individuals (17,444/24,570) receiving GS as their primary test. An estimated false negative rate of 0.3% could be expected. Conclusions GS can capture clinically relevant germline variants in a 'GS-first strategy' for the majority of clinical indications in a genetics diagnostic lab. Keywords: Rare disease, Genome sequencing, Impact modeling, Reducing workflow complexity, Genetic diagnostic laboratories, Germline variant detection