Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability.
Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability.
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DOI：
10.1371/journal.pone.0256181
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
FitzPatrick DR
中科院分区：
文献类型：
--
作者：
Bengani H;Grozeva D;Moyon L;Bhatia S;Louros SR;Hope J;Jackson A;Prendergast JG;Owen LJ;Naville M;Rainger J;Grimes G;Halachev M;Murphy LC;Spasic-Boskovic O;van Heyningen V;Kind P;Abbott CM;Osterweil E;Raymond FL;Roest Crollius H;FitzPatrick DR
事实证明，在神经发育障碍中识别顺式调节元件(Cre)的致病变异是具有挑战性的。我们使用体内功能分析对临床队列中经过严格筛选的Cre变异进行分类，该队列似乎富含致病Cre突变：48名无血缘关系的男性，其家族史与X连锁智力残疾(XLID)一致，在X染色体编码区(ChrX)无法发现可检测到的原因。对所有chrX Cre进行定向测序，在5个受影响的个体中发现了6个罕见的变异，这些变异改变了Cre中针对已知XLID基因的保守碱基，并在家族中适当分离。其中两个变异体，FMR1CRE和TENM1CRE，用双色荧光报告实验显示斑马鱼大脑发育中增强子功能的位置和阶段特异性一致的差异。为这两种变种都创建了小鼠模型。在雄性小鼠中，Fmr1CRE诱导了神经发育Fmr1表达、嗅觉行为和FMRP功能的神经生理指标的变化。在全基因组测序中缺乏另一个可能的致病变异进一步支持FMR1CRE作为该家族中XLID的可能基础。Tenm1CRE小鼠没有表现出表型异常。在gnomAD 2.1发布后，重新分析显示TENM1CRE超过了XLID致病等位基因的最大可能群体频率。将致病状态分配给任何超罕见的Cre变异体仍然是有问题的，并且需要来自多个来源的与疾病相关的体内功能数据。这种分析的顺序和定制性质使得它们既耗时又具有挑战性，难以扩展到常规的临床使用。
Identifying causative variants in cis-regulatory elements (CRE) in neurodevelopmental disorders has proven challenging. We have used in vivo functional analyses to categorize rigorously filtered CRE variants in a clinical cohort that is plausibly enriched for causative CRE mutations: 48 unrelated males with a family history consistent with X-linked intellectual disability (XLID) in whom no detectable cause could be identified in the coding regions of the X chromosome (chrX). Targeted sequencing of all chrX CRE identified six rare variants in five affected individuals that altered conserved bases in CRE targeting known XLID genes and segregated appropriately in families. Two of these variants, FMR1CRE and TENM1CRE, showed consistent site- and stage-specific differences of enhancer function in the developing zebrafish brain using dual-color fluorescent reporter assay. Mouse models were created for both variants. In male mice Fmr1CRE induced alterations in neurodevelopmental Fmr1 expression, olfactory behavior and neurophysiological indicators of FMRP function. The absence of another likely causative variant on whole genome sequencing further supported FMR1CRE as the likely basis of the XLID in this family. Tenm1CRE mice showed no phenotypic anomalies. Following the release of gnomAD 2.1, reanalysis showed that TENM1CRE exceeded the maximum plausible population frequency of a XLID causative allele. Assigning causative status to any ultra-rare CRE variant remains problematic and requires disease-relevant in vivo functional data from multiple sources. The sequential and bespoke nature of such analyses renders them time-consuming and challenging to scale for routine clinical use.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
16
作者：
Calo, Eliezer;Wysocka, Joanna
通讯作者：
Wysocka, Joanna
影响因子：
4.5
作者：
McEwen GK;Goode DK;Parker HJ;Woolfe A;Callaway H;Elgar G
通讯作者：
Elgar G
影响因子：
30.8
作者：
Mifsud, Borbala;Tavares-Cadete, Filipe;Osborne, Cameron S.
通讯作者：
Osborne, Cameron S.
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.