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

Abstract

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.

Fig. 1. Flow scheme of the study of the performance of GS as first-tier test for neurodevelopmental disorders.

All prospectively included patients and their parents received genome sequencing and the exome sequencing-based SOC work-up, supplemented with genomic microarray profiling and gene-by-gene testing upon request, allowing for a direct comparison of the performance of both pathways.

Fig. 2. Genomic alignment of CHD2 and AHDC1 CNVs in genome sequencing data.

Visualization of genomic alignment of GS data in the Integrative Genomics Viewer (IGV) software for two CNVs that were detected by GS only. A 5 kb deletion in CHD2 at 15q26.1(93494184-93499518)x1 (patient 33), encompassing exon 14 and 15. B 36 kb deletion in AHDC1 at 1p36.11(27833526-27869757)x1 (patient 47), including the (non-coding) exon 9 (3′UTR). CNVs are visible from multiple lines of evidence, including read depth (A + B; arrow) and read pairs with larger than expected insert size (A; reads in red).