AutoCaSc: Prioritizing candidate genes for neurodevelopmental disorders.

IF 3.3 2区医学 Q2 GENETICS & HEREDITY

Human Mutation Pub Date : 2022-12-01 DOI:10.1002/humu.24451

Johann Kaspar Lieberwirth, Benjamin Büttner, Chiara Klöckner, Konrad Platzer, Bernt Popp, Rami Abou Jamra

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引用次数: 6

Abstract

Routine exome sequencing (ES) in individuals with neurodevelopmental disorders (NDD) remains inconclusive in >50% of the cases. Research analysis of unsolved cases can identify novel candidate genes but is time-consuming, subjective, and hard to compare between labs. The field, therefore, requires automated and standardized assessment methods to prioritize candidates for matchmaking. We developed AutoCaSc (https://autocasc.uni-leipzig.de) based on our candidate scoring scheme. We validated our approach using synthetic trios and real in-house trio ES data. AutoCaSc consistently (94.5% of all cases) scored the relevant 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 high-scoring variants missed in manual evaluation. It identified candidate variants in previously undescribed NDD candidate genes (CNTN2, DLGAP1, SMURF1, NRXN3, and 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 the 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.

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AutoCaSc:优选神经发育障碍的候选基因。

神经发育障碍(NDD)患者的常规外显子组测序(ES)在>50%的病例中仍然没有定论。对未解决病例的研究分析可以确定新的候选基因，但耗时、主观，而且难以在实验室之间进行比较。因此，该领域需要自动化和标准化的评估方法来优先考虑配对的候选人。我们根据候选评分方案开发了AutoCaSc (https://autocasc.uni-leipzig.de)。我们使用合成三重奏和真实的内部三重奏ES数据验证了我们的方法。AutoCaSc一致(占所有病例的94.5%)将有效的新型NDD基因的相关变异评分在前三名中。在93个真实的三人外显子组中，AutoCaSc识别了大多数(97.5%)先前手工评分的变异，同时评估了手工评估中遗漏的其他高分变异。该研究发现了先前描述的NDD候选基因(CNTN2、DLGAP1、SMURF1、NRXN3和PRICKLE1)的候选变异。AutoCaSc使任何人都能够快速筛选NDD中的变体的合理性。在提供了超过40个ndd相关基因的描述后，我们根据我们丰富的经验提供了使用建议。我们的实现能够管道整合，因此允许筛选候选基因的大队列。AutoCaSc使小型实验室能够进行标准化的配对协作，并为持续识别新的NDD实体做出贡献。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Human Mutation 医学-遗传学

CiteScore

8.40

自引率

5.10%

发文量

190

审稿时长

2 months

期刊介绍： Human Mutation is a peer-reviewed journal that offers publication of original Research Articles, Methods, Mutation Updates, Reviews, Database Articles, Rapid Communications, and Letters on broad aspects of mutation research in humans. Reports of novel DNA variations and their phenotypic consequences, reports of SNPs demonstrated as valuable for genomic analysis, descriptions of new molecular detection methods, and novel approaches to clinical diagnosis are welcomed. Novel reports of gene organization at the genomic level, reported in the context of mutation investigation, may be considered. The journal provides a unique forum for the exchange of ideas, methods, and applications of interest to molecular, human, and medical geneticists in academic, industrial, and clinical research settings worldwide.