TY - JOUR
T1 - The performance of genome sequencing as a first-tier test for neurodevelopmental disorders
AU - van der Sanden, Bart P G H
AU - Schobers, Gaby
AU - Corominas Galbany, Jordi
AU - Koolen, David A
AU - Sinnema, Margje
AU - van Reeuwijk, Jeroen
AU - Stumpel, Connie T R M
AU - Kleefstra, Tjitske
AU - de Vries, Bert B A
AU - Ruiterkamp-Versteeg, Martina
AU - Leijsten, Nico
AU - Kwint, Michael
AU - Derks, Ronny
AU - Swinkels, Hilde
AU - den Ouden, Amber
AU - Pfundt, Rolph
AU - Rinne, Tuula
AU - de Leeuw, Nicole
AU - Stegmann, Alexander P
AU - Stevens, Servi J
AU - van den Wijngaard, Arthur
AU - Brunner, Han G
AU - Yntema, Helger G
AU - Gilissen, Christian
AU - Nelen, Marcel R
AU - Vissers, Lisenka E L M
N1 - © 2022. The Author(s).
PY - 2023/1
Y1 - 2023/1
N2 - Genome sequencing (GS) can identify novel diagnoses for patients who remain undiagnosed after routine diagnostic procedures. We tested whether GS is a better first-tier genetic diagnostic test than current standard of care (SOC) by assessing the technical and clinical validity of GS for patients with neurodevelopmental disorders (NDD). We performed both GS and exome sequencing in 150 consecutive NDD patient-parent trios. The primary outcome was diagnostic yield, calculated from disease-causing variants affecting exonic sequence of known NDD genes. GS (30%, n = 45) and SOC (28.7%, n = 43) had similar diagnostic yield. All 43 conclusive diagnoses obtained with SOC testing were also identified by GS. SOC, however, required integration of multiple test results to obtain these diagnoses. GS yielded two more conclusive diagnoses, and four more possible diagnoses than ES-based SOC (35 vs. 31). Interestingly, these six variants detected only by GS were copy number variants (CNVs). Our data demonstrate the technical and clinical validity of GS to serve as routine first-tier genetic test for patients with NDD. Although the additional diagnostic yield from GS is limited, GS comprehensively identified all variants in a single experiment, suggesting that GS constitutes a more efficient genetic diagnostic workflow.
AB - Genome sequencing (GS) can identify novel diagnoses for patients who remain undiagnosed after routine diagnostic procedures. We tested whether GS is a better first-tier genetic diagnostic test than current standard of care (SOC) by assessing the technical and clinical validity of GS for patients with neurodevelopmental disorders (NDD). We performed both GS and exome sequencing in 150 consecutive NDD patient-parent trios. The primary outcome was diagnostic yield, calculated from disease-causing variants affecting exonic sequence of known NDD genes. GS (30%, n = 45) and SOC (28.7%, n = 43) had similar diagnostic yield. All 43 conclusive diagnoses obtained with SOC testing were also identified by GS. SOC, however, required integration of multiple test results to obtain these diagnoses. GS yielded two more conclusive diagnoses, and four more possible diagnoses than ES-based SOC (35 vs. 31). Interestingly, these six variants detected only by GS were copy number variants (CNVs). Our data demonstrate the technical and clinical validity of GS to serve as routine first-tier genetic test for patients with NDD. Although the additional diagnostic yield from GS is limited, GS comprehensively identified all variants in a single experiment, suggesting that GS constitutes a more efficient genetic diagnostic workflow.
U2 - 10.1038/s41431-022-01185-9
DO - 10.1038/s41431-022-01185-9
M3 - Article
C2 - 36114283
SN - 1018-4813
VL - 31
SP - 81
EP - 88
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 1
ER -