Computational analysis of 10,860 phenotypic annotations in individuals with SCN2A-related disorders.
Computational analysis of 10,860 phenotypic annotations in individuals with SCN2A-related disorders.
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DOI：
10.1038/s41436-021-01120-1
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Helbig I
中科院分区：
文献类型：
--
作者：
Crawford K;Xian J;Helbig KL;Galer PD;Parthasarathy S;Lewis-Smith D;Kaufman MC;Fitch E;Ganesan S;O'Brien M;Codoni V;Ellis CA;Conway LJ;Taylor D;Krause R;Helbig I
SCN2A的致病变异导致了广泛的神经发育表型。关于基因-表型相关性的报道往往是轶事，而且现有的表型数据还没有得到系统的分析。我们从2001年至2019年文献中对SCN2A相关疾病的主要描述中提取表型信息，并以人类表型本体(HPO)术语编码。通过HPO结构推断的更高水平的表型术语，我们评估了临床特征的频率，并研究了这些特征与NaV1.2蛋白中不同类别和位置的关联。我们识别了413个不相关的个体，得出了总共10,860个HPO术语和562个唯一术语。蛋白质截断变异与自闭症和行为异常有关。错义变异与新生儿发病、癫痫痉挛和癫痫发作有关，无论是哪种类型。在62个复发的SCN2A变异体中，有8个发现了表型相似性。三个独立的主成分解释了33%的表型变异，允许以良好的性能分离功能增益和功能丧失变体。我们的工作表明，使用标准化语言将临床特征转换为可计算的格式，可以进行定量的表型分析，以前所未有的细节绘制SCN2A相关疾病的表型图谱，并揭示多维谱上的基因型-表型相关性。
Pathogenic variants in SCN2A cause a wide range of neurodevelopmental phenotypes. Reports of genotype–phenotype correlations are often anecdotal, and the available phenotypic data have not been systematically analyzed. We extracted phenotypic information from primary descriptions of SCN2A-related disorders in the literature between 2001 and 2019, which we coded in Human Phenotype Ontology (HPO) terms. With higher-level phenotype terms inferred by the HPO structure, we assessed the frequencies of clinical features and investigated the association of these features with variant classes and locations within the NaV1.2 protein. We identified 413 unrelated individuals and derived a total of 10,860 HPO terms with 562 unique terms. Protein-truncating variants were associated with autism and behavioral abnormalities. Missense variants were associated with neonatal onset, epileptic spasms, and seizures, regardless of type. Phenotypic similarity was identified in 8/62 recurrent SCN2A variants. Three independent principal components accounted for 33% of the phenotypic variance, allowing for separation of gain-of-function versus loss-of-function variants with good performance. Our work shows that translating clinical features into a computable format using a standardized language allows for quantitative phenotype analysis, mapping the phenotypic landscape of SCN2A-related disorders in unprecedented detail and revealing genotype–phenotype correlations along a multidimensional spectrum.
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影响因子：
14.9
作者：
Liu, Cong;Kury, Fabricio Sampaio Peres;Weng, Chunhua
通讯作者：
Weng, Chunhua
DOI：
10.1038/s41436-020-0923-1
发表时间：
2020-12
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Ganesan S;Galer PD;Helbig KL;McKeown SE;O'Brien M;Gonzalez AK;Felmeister AS;Khankhanian P;Ellis CA;Helbig I
通讯作者：
Helbig I
影响因子：
9.8
作者：
Helbig, Ingo;Lopez-Hernandez, Tania;White, Peter
通讯作者：
White, Peter
影响因子：
30.8
作者：
Heyne, Henrike O.;Singh, Tarjinder;Lemke, Johannes R.
通讯作者：
Lemke, Johannes R.
影响因子：
3.9
作者：
Lauxmann, Stephan;Verbeek, Nienke E.;Hedrich, Ulrike B. S.
通讯作者：
Hedrich, Ulrike B. S.