MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia.
MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia.
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DOI：
10.1002/mds.29147
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发表时间：
2022-10
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尽管下一代测序技术取得了进展，但识别不确定意义的变体（VUS）通常会阻碍复杂神经发育障碍患者的明确诊断。本研究的目的是确定和描述一个有两个孩子的家庭的疾病的根本原因，这些孩子患有与全身性肌张力障碍和阵发性肌张力障碍状态、舞蹈病、癫痫和白内障相关的严重发育迟缓。使用细胞和脊椎动物模型系统表征通过自体接合性作图和全外显子组测序鉴定的候选基因。在三个候选基因中发现了纯合变体：MED 27、SLC 6A 7和MPPE 1。尽管患者具有MED 27相关疾病的特征，但对SLC 6A 7和MPPE 1变体进行了功能研究。SLC 6A 7变体在体外过表达由于细胞表面表达减少而导致脯氨酸转运减少，并且slc 6a 7的斑马鱼敲低表现出发育延迟和脆弱的运动神经元形态，其不能被L-脯氨酸转运蛋白-G396 S RNA拯救。最后，患者成纤维细胞显示与MPPE 1功能障碍相关的糖磷脂酰肌醇锚定蛋白的细胞表面表达减少。我们报告了一个携带纯合MED 27变异体的家族，该变异体具有额外的SLC 6A 7和MPPE 1基因变异体功能丧失，这可能导致由多位点致病性变异体引起的混合表型。版权所有© 2022作者。运动障碍由Wiley Periodicals LLC代表国际帕金森和运动障碍协会出版
Despite advances in next generation sequencing technologies, the identification of variants of uncertain significance (VUS) can often hinder definitive diagnosis in patients with complex neurodevelopmental disorders. The objective of this study was to identify and characterize the underlying cause of disease in a family with two children with severe developmental delay associated with generalized dystonia and episodic status dystonicus, chorea, epilepsy, and cataracts. Candidate genes identified by autozygosity mapping and whole‐exome sequencing were characterized using cellular and vertebrate model systems. Homozygous variants were found in three candidate genes: MED27, SLC6A7, and MPPE1. Although the patients had features of MED27‐related disorder, the SLC6A7 and MPPE1 variants were functionally investigated. SLC6A7 variant in vitro overexpression caused decreased proline transport as a result of reduced cell‐surface expression, and zebrafish knockdown of slc6a7 exhibited developmental delay and fragile motor neuron morphology that could not be rescued by L‐proline transporter–G396S RNA. Lastly, patient fibroblasts displayed reduced cell‐surface expression of glycophosphatidylinositol‐anchored proteins linked to MPPE1 dysfunction. We report a family harboring a homozygous MED27 variant with additional loss‐of‐function SLC6A7 and MPPE1 gene variants, which potentially contribute to a blended phenotype caused by multilocus pathogenic variants. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society