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AutoCaSc: Prioritizing candidate genes for neurodevelopmental disorders
  • +3
  • Johann Lieberwirth,
  • Benjamin Büttner,
  • Chiara Klöckner,
  • Konrad Platzer,
  • Bernt Popp,
  • Rami Abou Jamra
Johann Lieberwirth
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig 04103, Germany
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Benjamin Büttner
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig 04103, Germany
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Chiara Klöckner
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig 04103, Germany
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Konrad Platzer
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig 04103, Germany
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Bernt Popp
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig 04103, Germany

Corresponding Author:bernt.popp@medizin.uni-leipzig.de

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Rami Abou Jamra
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig 04103, Germany
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Abstract

Routine exome sequencing (ES) in individuals with neurodevelopmental disorders (NDD) remains inconclusive in >50%. Research analysis of unsolved cases can identify novel candidate genes but is time consuming, subjective, and hard to compare between labs. The field therefore needs automated and standardized assessment methods to prioritize candidates for matchmaking. We developed AutoCaSc (https://autocasc.uni-leipzig.de) based on our candidate scoring scheme (CaSc). We validated our approach using synthetic trios and real in-house trio ES data. AutoCaSc consistently (94.5%) scored variants in valid novel NDD genes in the top three ranks. In 93 real trio exomes, AutoCaSc identified most (97.5%) previously manually scored variants while evaluating additional highly scoring variants missed in manual evaluation. It identified candidate variants in previously undescribed NDD candidate genes ( CNTN2, DLGAP1, SMURF1, NRXN3, PRICKLE1). AutoCaSc enables anybody to quickly screen a variant for its plausibility in NDD. After contributing >40 descriptions of NDD associated genes, we provide usage recommendations based on our extensive experience. Our implementation is capable of pipeline integration and therefore allows screening of large cohorts for candidate genes. AutoCaSc empowers even small labs to a standardized matchmaking collaboration and to contribute to the ongoing identification of novel NDD entities.
27 Apr 2022Submitted to Human Mutation
28 Apr 2022Submission Checks Completed
28 Apr 2022Assigned to Editor
04 May 2022Reviewer(s) Assigned
02 Jun 2022Review(s) Completed, Editorial Evaluation Pending
03 Jun 2022Editorial Decision: Revise Major
25 Jul 20221st Revision Received
25 Jul 2022Submission Checks Completed
25 Jul 2022Assigned to Editor
25 Jul 2022Reviewer(s) Assigned
17 Aug 2022Review(s) Completed, Editorial Evaluation Pending
18 Aug 2022Editorial Decision: Accept
14 Sep 2022Published in Human Mutation. 10.1002/humu.24451