Programmpunkt

15:10–15:12

Titel: "Pan-Nephro" comprehensive genetic testing for all kidney diseases: Premium performance in difficult-to-target regions – Quality is key
ID: P-ClinG-053
Art: Postertalk
Redezeit: 2 min
Session: Poster Session
ClinG

Referent: Valeska Frank (Mainz/DE)


Abstract - Text

Abstract-Text

We have developed an optimized diagnostic pan-nephro approach - covering all genes (>600) known to be causative for any kind of kidney disease - to enable comprehensive genetic testing for all kidney diseases including differential diagnosis. Instead of extracting virtual panels out of a whole exome approach, we continuously update the existing design based on curated literature, expert knowledge and variant databases (e.g. HGMD, ClinVar).


Notably, out-of-the-shelf WES products lack specific adaptions of the design in difficult-to-target regions as well as non-coding variants reported to be clinically relevant. Awareness of technical limitations of available testing kits and of the presence of complex nature in critical genes requires in depth knowledge about the underlying genomic regions and pathomechanisms. Many genes responsible for kidney disorders are greatly demanding due to the presence of highly homologous sequences. For example, the PKD1 gene, the major gene for autosomal dominant polycystic kidney disease (ADPKD), has six pseudogenes hampering unambiguous variant calling. Major challenges are also posed by sequence and copy number variations (CNVs) in the human CFH gene cluster within the RCA (regulators of complement activity) region linked to C3 glomerulopathy and thromobotic microangiopathies such as atypical haemolytic uremic syndrome (aHUS).


In our customized approach, we specifically target these regions by optimizing target size and bait composition including non-coding regions for optimal variant calling. Sequencing at higher coverage and validating the bioinformatic processing of the data, we demonstrate significantly improved performance and sensitivity for small and complex sequence alterations including CNVs and genomic rearrangements.


In conclusion, our approach enables high-performance and fast-track analysis of all kidney disease genes decisive for genetic testing of complex and difficult-to-target regions.