The performance of genome sequencing as a first-tier test for neurodevelopmental disorders

Bart P G H van der Sanden, Gaby Schobers, Jordi Corominas Galbany, David A Koolen, Margje Sinnema, Jeroen van Reeuwijk, Connie T R M Stumpel, Tjitske Kleefstra, Bert B A de Vries, Martina Ruiterkamp-Versteeg, Nico Leijsten, Michael Kwint, Ronny Derks, Hilde Swinkels, Amber den Ouden, Rolph Pfundt, Tuula Rinne, Nicole de Leeuw, Alexander P Stegmann, Servi J StevensArthur van den Wijngaard, Han G Brunner, Helger G Yntema, Christian Gilissen, Marcel R Nelen, Lisenka E L M Vissers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)81-88
Number of pages8
JournalEuropean Journal of Human Genetics
Issue number1
Early online date16 Sept 2022
Publication statusPublished - Jan 2023


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