TY - JOUR T1 - Scientific evaluation of negative exome sequencing followed by systematic scoring of candidate genes to decipher the genetics of neurodevelopmental disorders JF - bioRxiv DO - 10.1101/588517 SP - 588517 AU - Benjamin Büttner AU - Sonja Martin AU - Anja Finck AU - Maria Arelin AU - Carolin Baade-Büttner AU - Tobias Bartolomaeus AU - Peter Bauer AU - Astrid Bertsche AU - Matthias K. Bernhard AU - Saskia Biskup AU - Nataliya Di Donato AU - Magdeldin Elgizouli AU - Roland Ewald AU - Constanze Heine AU - Yorck Hellenbroich AU - Julia Hentschel AU - Sabine Hoffjan AU - Susanne Horn AU - Frauke Hornemann AU - Dagmar Huhle AU - Susanne B. Kamphausen AU - Wieland Kiess AU - Ilona Krey AU - Alma Kuechler AU - Ben Liesfeld AU - Andreas Merkenschlager AU - Diana Mitter AU - Petra Muschke AU - Roland Pfäffle AU - Tilman Polster AU - Ina Schanze AU - Jan-Ulrich Schlump AU - Steffen Syrbe AU - Dagmar Wieczorek AU - Martin Zenker AU - Johannes R. Lemke AU - Diana Le Duc AU - Konrad Platzer AU - Rami Abou Jamra Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/03/26/588517.abstract N2 - Background Deciphering 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.Methods We 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.Results In 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.Conclusions We 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. ER -