TY - JOUR
T1 - Genome sequencing as a generic diagnostic strategy for rare disease
AU - Schobers, Gaby
AU - Derks, Ronny
AU - den Ouden, Amber
AU - Swinkels, Hilde
AU - van Reeuwijk, Jeroen
AU - Bosgoed, Ermanno
AU - Lugtenberg, Dorien
AU - Sun, Su Ming
AU - Corominas Galbany, Jordi
AU - Weiss, Marjan
AU - Blok, Marinus J
AU - Olde Keizer, Richelle A C M
AU - Hofste, Tom
AU - Hellebrekers, Debby
AU - de Leeuw, Nicole
AU - Stegmann, Alexander
AU - Kamsteeg, Erik-Jan
AU - Paulussen, Aimee D C
AU - Ligtenberg, Marjolijn J L
AU - Bradley, Xiangqun Zheng
AU - Peden, John
AU - Gutierrez, Alejandra
AU - Pullen, Adam
AU - Payne, Tom
AU - Gilissen, Christian
AU - van den Wijngaard, Arthur
AU - Brunner, Han G
AU - Nelen, Marcel
AU - Yntema, Helger G
AU - Vissers, Lisenka E L M
PY - 2024/2/14
Y1 - 2024/2/14
N2 - 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™6000; 150 bp paired-end reads, 37?×?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?=?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.
AB - 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™6000; 150 bp paired-end reads, 37?×?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?=?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.
KW - Genetic diagnostic laboratories
KW - Genome sequencing
KW - Germline variant detection
KW - Impact modeling
KW - Rare disease
KW - Reducing workflow complexity
KW - Humans
KW - Rare Diseases/diagnosis genetics
KW - Whole Genome Sequencing
KW - Base Sequence
KW - Chromosome Mapping
KW - Exome Sequencing
KW - High-Throughput Nucleotide Sequencing
U2 - 10.1186/s13073-024-01301-y
DO - 10.1186/s13073-024-01301-y
M3 - Article
SN - 1756-994X
VL - 16
JO - Genome Medicine
JF - Genome Medicine
IS - 1
M1 - 32
ER -