Titel: Diagnostic yield of trio genome sequencing as first-tier analysis for rare diseases
ID: P-MonoG-146
Art: Postertalk nominated
Redezeit: 3 min
Session: Poster Session
Nominated posters presentation

Referent: Rebecca Buchert (Tübingen/DE)

Abstract - Text



Whole exome sequencing (WES) has greatly enhanced the diagnostic yield for rare syndromic disorders over the last years. Still, depending on the study population up to 60% of cases remain unsolved after WES. In this study we sought to improve the diagnostic yield by performing trio genome sequencing as a first-tier diagnostics.


We performed diagnostic genome sequencing on a NovaSeq6000 platform (Illumina) using the TruSeq PCR-free kit (Illumina) on 109 patient-parent trios with rare diseases, mainly intellectual disability, who had not undergone previous NGS analysis. Data analysis was performed using our in-house pipeline GSVar filtering for rare single nucleotide, copy number and structural variants which either occurred de novo or were inherited in a recessive manner.


With our trio approach we could identify a clear pathogenic variant in 40% of cases, strong variants of unknown significance in 16% of cases and 4 potential new candidate genes pending further follow-up.

Genome sequencing was not only efficient in identifying single nucleotide variants (SNVs) but also facilitated the detection of copy number variants (CNVs) in 13% of cases and more complex structural variants (SVs) in 3% of cases. CNV detection with genome sequencing proved to be more comprehensive than array analysis, since the exact breakpoint could be detected in most cases and smaller CNVs which would have been missed by array analysis were still easily detected. The detected causative variants occurred de novo in 67% of cases and were thus easily identified and classified with our trio approach.

Nevertheless, we were still unable to identify pathogenic variants in 41% of cases. The biggest issue we encountered was the interpretation of deep intronic or intergenic variation. Therefore, we are planning on performing transcriptome analysis on the unsolved cases to elucidate the effects of these variants on transcription and improve their interpretation in the future.


In summary, our trio genome approach proved to have a high efficiency in detecting pathogenic single nucleotide, copy number and structural variants in rare diseases and can be applied as a first-tier method in genetic diagnostics.