Scientific evaluation of negative exome sequencing followed by systematic scoring of candidate genes to decipher the genetics of neurodevelopmental disorders
Scientific evaluation of negative exome sequencing followed by systematic scoring of candidate genes to decipher the genetics of neurodevelopmental disorders
Abstract BackgroundDeciphering 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.
Muschke Petra、Kuechler Alma、Arelin Maria、Syrbe Steffen、Zenker Martin、Platzer Konrad、B¨1ttner Benjamin、Bernhard Matthias K.、Elgizouli Magdeldin、Ewald Roland、Heine Constanze、Hentschel Julia、Huhle Dagmar、Kamphausen Susanne B.、Kiess Wieland、Liesfeld Ben、Mitter Diana、Horn Susanne、Jamra Rami Abou、Wieczorek Dagmar、Merkenschlager Andreas、Donato Nataliya Di、Bauer Peter、Pf?ffle Roland、Schlump Jan-Ulrich、Hellenbroich Yorck、Bartolomaeus Tobias、Lemke Johannes R.、Schanze Ina、Krey Ilona、Hoffjan Sabine、Hornemann Frauke、Duc Diana Le、Polster Tilman、Biskup Saskia、Finck Anja、Bertsche Astrid、Martin Sonja、Baade-B¨1ttner Carolin
Institute of Human Genetics, University Hospital MagdeburgInstitute of Human Genetics, University Hospital EssenHospital for Children and Adolescents, University of Leipzig Medical CenterDivision for Neuropaediatrics and Metabolic Medicine, Center for Paediatric and Adolescent Medicine, Heidelberg University HospitalInstitute of Human Genetics, University Hospital MagdeburgInstitute of Human Genetics, University of Leipzig Medical CenterInstitute of Human Genetics, University of Leipzig Medical CenterHospital for Children and Adolescents, University of Leipzig Medical CenterInstitute of Human Genetics, University Hospital EssenLimbus Medical Technologies GmbHInstitute of Human Genetics, University of Leipzig Medical CenterInstitute of Human Genetics, University of Leipzig Medical CenterPraxis f¨1r Humangenetik LeipzigInstitute of Human Genetics, University Hospital MagdeburgHospital for Children and Adolescents, University of Leipzig Medical CenterLimbus Medical Technologies GmbHInstitute of Human Genetics, University of Leipzig Medical CenterInstitute of Human Genetics, University of Leipzig Medical CenterInstitute of Human Genetics, University of Leipzig Medical CenterInstitute of Human Genetics, Medical Faculty, Heinrich-Heine-University D¨1sseldorfHospital for Children and Adolescents, University of Leipzig Medical CenterInstitute of Clinical Genetics, Technische Universit?t DresdenCentogene AGHospital for Children and Adolescents, University of Leipzig Medical CenterInstitute of Human Genetics, University of Leipzig Medical CenterInstitute of Human Genetics, University L¨1beckInstitute of Human Genetics, University of Leipzig Medical CenterInstitute of Human Genetics, University of Leipzig Medical CenterInstitute of Human Genetics, University Hospital MagdeburgInstitute of Human Genetics, University of Leipzig Medical CenterDepartment of Human Genetics, Ruhr-UniversityHospital for Children and Adolescents, University of Leipzig Medical CenterInstitute of Human Genetics, University of Leipzig Medical CenterPaediatric Epileptology, Mara Hospital gGmbH, Bethel Epilepsy CenterCeGaT GmbH, Center for Genomics and TranscriptomicsInstitute of Human Genetics, University of Leipzig Medical CenterHospital for Children and Adolescents, University of Leipzig Medical CenterInstitute of Human Genetics, University of Leipzig Medical CenterDepartment of Neurology, University of Leipzig Medical Center
医学研究方法神经病学、精神病学基础医学
Exome sequencingNDDmental retardationCandidate geneScoringintellectual disability
Muschke Petra,Kuechler Alma,Arelin Maria,Syrbe Steffen,Zenker Martin,Platzer Konrad,B¨1ttner Benjamin,Bernhard Matthias K.,Elgizouli Magdeldin,Ewald Roland,Heine Constanze,Hentschel Julia,Huhle Dagmar,Kamphausen Susanne B.,Kiess Wieland,Liesfeld Ben,Mitter Diana,Horn Susanne,Jamra Rami Abou,Wieczorek Dagmar,Merkenschlager Andreas,Donato Nataliya Di,Bauer Peter,Pf?ffle Roland,Schlump Jan-Ulrich,Hellenbroich Yorck,Bartolomaeus Tobias,Lemke Johannes R.,Schanze Ina,Krey Ilona,Hoffjan Sabine,Hornemann Frauke,Duc Diana Le,Polster Tilman,Biskup Saskia,Finck Anja,Bertsche Astrid,Martin Sonja,Baade-B¨1ttner Carolin.Scientific evaluation of negative exome sequencing followed by systematic scoring of candidate genes to decipher the genetics of neurodevelopmental disorders[EB/OL].(2025-03-28)[2025-05-01].https://www.biorxiv.org/content/10.1101/588517.点此复制
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