Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment.
Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment.
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DOI：
10.1038/s41380-020-0858-6
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发表时间：
2021-07
影响因子：
11
通讯作者：
Hipp JF
中科院分区：
文献类型：
--
作者：
Keute M;Miller MT;Krishnan ML;Sadhwani A;Chamberlain S;Thibert RL;Tan WH;Bird LM;Hipp JF
安格尔曼综合征（AS）是一种由于神经元中UBE 3A表达受损而导致的严重神经发育障碍。有几种遗传机制会损害UBE 3A的表达，但它们在如何影响15号染色体15 q11-q13上的相邻基因方面有所不同。有证据表明，不同的基因亚型具有不同的临床严重程度，但缺乏系统的定量研究。在这里，我们分析了大样本的个人与AS的自然历史数据（n = 250，848项评估），包括量化运动、认知和语言技能发展的临床量表（Bayley婴儿发育量表，第三版;学龄前语言量表，第四版）、适应行为（Vineland适应行为量表，第二版）和AS特异性症状（AS临床严重程度量表）。我们发现，临床严重程度，如这些量表所捕获的，在遗传亚型之间存在差异：具有UBE 3A致病性变体和印迹缺陷（IPD）的个体比具有单亲父系二体性（UPD）的个体受影响更小;在具有UBE 3A致病性变体的个体中，具有截短突变的个体比具有错义突变的个体受损更大。包含UBE 3A和其他基因缺失的个体受损最严重，但与以前的工作相比，我们几乎没有发现缺失长度（I类与II类）对表现严重程度影响的证据。这项系统分析的结果突出了UBE 3A以外的基因组区域作为AS表型的贡献因素的相关性，并为开发AS的新疗法提供了重要信息。更一般地说，这项工作阐明了如何增加遗传不规则性反映在临床严重程度。
Angelman Syndrome (AS) is a severe neurodevelopmental disorder due to impaired expression of UBE3A in neurons. There are several genetic mechanisms that impair UBE3A expression, but they differ in how neighboring genes on chromosome 15 at 15q11–q13 are affected. There is evidence that different genetic subtypes present with different clinical severity, but a systematic quantitative investigation is lacking. Here we analyze natural history data on a large sample of individuals with AS (n = 250, 848 assessments), including clinical scales that quantify development of motor, cognitive, and language skills (Bayley Scales of Infant Development, Third Edition; Preschool Language Scale, Fourth Edition), adaptive behavior (Vineland Adaptive Behavioral Scales, Second Edition), and AS-specific symptoms (AS Clinical Severity Scale). We found that clinical severity, as captured by these scales, differs between genetic subtypes: individuals with UBE3A pathogenic variants and imprinting defects (IPD) are less affected than individuals with uniparental paternal disomy (UPD); of those with UBE3A pathogenic variants, individuals with truncating mutations are more impaired than those with missense mutations. Individuals with a deletion that encompasses UBE3A and other genes are most impaired, but in contrast to previous work, we found little evidence for an influence of deletion length (class I vs. II) on severity of manifestations. The results of this systematic analysis highlight the relevance of genomic regions beyond UBE3A as contributing factors in the AS phenotype, and provide important information for the development of new therapies for AS. More generally, this work exemplifies how increasing genetic irregularities are reflected in clinical severity.
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影响因子：
4.8
作者：
Kuhnle, Simone;Martinez-Noel, Gustavo;Howley, Peter M.
通讯作者：
Howley, Peter M.
影响因子：
4.5
作者：
Ferreira, J. A.;Zwinderman, A. H.
通讯作者：
Zwinderman, A. H.
DOI：
10.1097/dbp.0b013e3181ee408e
发表时间：
2010-09-01
影响因子：
2.4
作者：
Gentile, Jennifer K.;Tan, Wen-Hann;Peters, Sarika U.
通讯作者：
Peters, Sarika U.
影响因子：
4
作者：
Sahoo, T.;Peters, S. U.;Bacino, C. A.
通讯作者：
Bacino, C. A.
影响因子：
5.2
作者：
Trillingsgaard, A;Ostergaard, JR
通讯作者：
Ostergaard, JR