Scientific evaluation of negative exome sequencing followed by systematic scoring of candidate genes to decipher the genetics of neurodevelopmental disorders
Author:
Büttner Benjamin, Martin Sonja, Finck Anja, Arelin Maria, Baade-Büttner Carolin, Bartolomaeus Tobias, Bauer Peter, Bertsche Astrid, Bernhard Matthias K., Biskup Saskia, Donato Nataliya Di, Elgizouli Magdeldin, Ewald Roland, Heine Constanze, Hellenbroich Yorck, Hentschel Julia, Hoffjan Sabine, Horn Susanne, Hornemann Frauke, Huhle Dagmar, Kamphausen Susanne B., Kiess Wieland, Krey Ilona, Kuechler Alma, Liesfeld Ben, Merkenschlager Andreas, Mitter Diana, Muschke Petra, Pfäffle Roland, Polster Tilman, Schanze Ina, Schlump Jan-Ulrich, Syrbe Steffen, Wieczorek Dagmar, Zenker Martin, Lemke Johannes R., Duc Diana Le, Platzer Konrad, Jamra Rami AbouORCID
Abstract
AbstractBackgroundDeciphering the monogenetic causes of neurodevelopmental disorders (NDD) is an important milestone to offer personalized care. But the plausibility of reported candidate genes in exome studies often remains unclear, which slows down progress in the field.MethodsWe performed exome sequencing (ES) in 198 cases of NDD. Cases that remained unresolved (n=135) were re-investigated in a research setting. We established a candidate scoring system (CaSc) based on 12 different parameters reflecting variant and gene attributes as well as current literature to rank and prioritize candidate genes.ResultsIn this cohort, we identified 158 candidate variants in 148 genes with CaSc ranging from 2 to 11.7. Only considering the top 15% of candidates, 14 genes were already published or funneled into promising validation studies.ConclusionsWe promote that in an approach of case by case re-evaluation of primarily negative ES, systematic and standardized scoring of candidate genes can and should be applied. This simple framework enables better comparison, prioritization, and communication of candidate genes within the scientific community. This would represent an enormous benefit if applied to the tens of thousands of negative ES performed in routine diagnostics worldwide and speed up deciphering the monogenetic causes of NDD.
Publisher
Cold Spring Harbor Laboratory
Reference30 articles.
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