Constraint and conservation of paired-type homeodomains predicts the clinical outcome of missense variants of uncertain significance.,Human Mutation

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Constraint and conservation of paired-type homeodomains predicts the clinical outcome of missense variants of uncertain significance.
Human Mutation ( IF 3.3 ) Pub Date : 2020-05-07 , DOI: 10.1002/humu.24034
Monica H N Thai _{1,

2} , Alison Gardner ₁ , Laura Redpath _{1,

2} , Tessa Mattiske _{1,

2} , Oliver Dearsley ₁ , Marie Shaw ₁ , Anneke T Vulto-van Silfhout ₃ , Rolph Pfundt ₃ , Joanne Dixon ₄ , Julie McGaughran ₅ , Luis A Pérez-Jurado _{2,

6,

7,

8} , Jozef Gécz _{1,

2,

6} , Cheryl Shoubridge _{1,

2}

Affiliation

The need to interpret the pathogenicity of novel missense variants of unknown significance identified in the homeodomain of X‐chromosome aristaless‐related homeobox (ARX ) gene prompted us to assess the utility of conservation and constraint across these domains in multiple genes compared to conventional in vitro functional analysis. Pathogenic missense variants clustered in the homeodomain of ARX contribute to intellectual disability (ID) and epilepsy, with and without brain malformation in affected males. Here we report novel c.1112G>A, p.Arg371Gln and c.1150C>T, p.Arg384Cys variants in male patients with ID and severe seizures. The third case of a male patient with a c.1109C>T, p.Ala370Val variant is perhaps the first example of ID and autism spectrum disorder (ASD), without seizures or brain malformation. We compiled data sets of pathogenic variants from ClinVar and presumed benign variation from gnomAD and demonstrated that the high levels of sequence conservation and constraint of benign variation within the homeodomain impacts upon the ability of publicly available in silico prediction tools to accurately discern likely benign from likely pathogenic variants in these data sets. Despite this, considering the inheritance patterns of the genes and disease variants with the conservation and constraint of disease variants affecting the homeodomain in conjunction with current clinical assessments may assist in predicting the pathogenicity of missense variants, particularly for genes with autosomal recessive and X‐linked patterns of disease inheritance, such as ARX . In vitro functional analysis demonstrates that the transcriptional activity of all three variants was diminished compared to ARX‐Wt. We review the associated phenotypes of the published cases of patients with ARX homeodomain variants and propose expansion of the ARX‐related phenotype to include severe ID and ASD without brain malformations or seizures. We propose that the use of the constraint and conservation data in conjunction with consideration of the patient phenotype and inheritance pattern may negate the need for the experimental functional validation currently required to achieve a diagnosis.

中文翻译：

配对型同源域的约束和保守预测意义不明的错义变异的临床结果。

需要解释在 X 染色体 aristaless 相关同源盒 ( ARX ) 基因的同源域中发现的具有未知意义的新型错义变异的致病性，这促使我们评估与常规体外相比，多个基因中跨这些域的保守和约束的效用功能分析。聚集在ARX同源域中的致病性错义变异导致智力障碍 (ID) 和癫痫，无论有无脑畸形。在这里，我们报告了患有 ID 和严重癫痫发作的男性患者的新型 c.1112G>A、p.Arg371Gln 和 c.1150C>T、p.Arg384Cys 变体。第三例具有 c.1109C>T、p.Ala370Val 变异的男性患者可能是 ID 和自闭症谱系障碍 (ASD) 的第一个例子，没有癫痫发作或脑畸形。我们编译了来自 ClinVar 的致病变异数据集，并推测来自 gnomAD 的良性变异，并证明同源域内的高水平序列保守性和良性变异的约束影响了公开可用的计算机预测工具准确区分可能良性和可能良性的能力。这些数据集中的致病变异。尽管如此，ARX。体外功能分析表明，与 ARX-Wt 相比，所有三种变体的转录活性均降低。我们回顾了已发表的 ARX 同源域变异患者病例的相关表型，并建议将 ARX 相关表型扩展到包括无脑畸形或癫痫发作的严重 ID 和 ASD。我们建议结合考虑患者表型和遗传模式使用约束和保守数据可能会否定目前实现诊断所需的实验功能验证的需要。

更新日期：2020-05-07

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