The Benefit of Genome Sequencing in Neurodevelopmental Disorders

Background/Purpose: Roughly, half of rare disorder remain elusive after exome sequencing (ES). However, the benefit of genome sequencing (GS) is still poorly defined.

Methods: We performed GS (trio in 90%) using standard wet-lab techniques in 300 individuals, who remained undiagnosed after ES. We used the software Emedgene, Varvis, and Expansion Hunter to analyze single nucleotide, small indel, repeat expansion, mitochondrial and copy number variants.

Results: We successfully solved 9% of the cases. We partially or possibly solved further 9%. Careful evaluation showed that a third of these solved cases clearly required GS and that ES is not sufficient to identify the relevant variant. Such cases were small copy number variants, repeat expansions and noncoding variants. In the other two thirds, GS solved the cases mostly due to trio design, or as it uncovered human errors in the initial ES analysis. Further factors were increase in public databases and improved software. Solving cases is by far easier if there is any kind of differential diagnoses provided by the clinician. Two major, but solvable inconveniences are the difficulty of evaluating noncoding variants and structural variants without gain or loss of DNA.

Conclusion: GS clearly outperforms ES in identifying copy number variants and repeat expansions. Further benefits with room for improvements are noncoding variants and structural variants. Thus, GS is the better first-line analysis as it has a higher yield and it avoids time-consuming step-by-step diagnostics.

Publikationsverlauf

Artikel online veröffentlicht:
08. Oktober 2024