Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency.
Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency.
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DOI：
10.1038/s41436-019-0657-0
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发表时间：
2020-03
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影响因子：
--
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中科院分区：
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Lamb-Shaffer综合征（LAMSHF）是一种神经发育障碍，在二十多名患者中描述，这些患者患有涉及SOX 5的杂合遗传改变，SOX 5是一种编码调节神经发生和其他离散发育过程中细胞命运和分化的转录因子的基因。迄今为止描述的遗传改变主要是微缺失。本研究的目的是增加我们对LAMSHF的了解，其临床和遗传谱，以及所涉及的病理生理机制。通过GeneMatcher和临床或遗传网络收集了41名携带各种类型SOX 5改变的新患者的临床和遗传数据。研究了所选取代的功能后果。微缺失和截短变异发生在整个SOX 5。相比之下，大多数错义变体聚集在关键SOX特异性高迁移率族结构域。后一种变体阻止SOX 5结合DNA并促进体外反式激活，而位于高迁移率组结构域之外的错义变体则没有。不同患者的临床表现和严重程度不同。没有发现明确的基因型-表型相关性，除了高迁移率组结构域以外的错义变体通常耐受性更好。这项研究扩展了与LAMSHF相关的临床和遗传谱，并巩固了SOX 5单倍不足导致不同程度的智力残疾，语言延迟和其他临床特征的证据。
Lamb–Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved. Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types of SOX5 alterations. Functional consequences of selected substitutions were investigated. Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype–phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated. This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.
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影响因子：
11.4
作者：
Lefebvre, V;Li, P;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
DOI：
10.1073/pnas.0806791105
发表时间：
2008-10-14
影响因子：
11.1
作者：
Kwan, Kenneth Y.;Lam, Mandy M. S.;Sestan, Nenad
通讯作者：
Sestan, Nenad
影响因子：
8.8
作者：
Rosenfeld, Jill A.;Ballif, Blake C.;Shaffer, Lisa G.
通讯作者：
Shaffer, Lisa G.
影响因子：
5.3
作者：
Han, Yu;Lefebvre, Veronique
通讯作者：
Lefebvre, Veronique
影响因子：
9.8
作者：
Li, Quan;Wang, Kai
通讯作者：
Wang, Kai