NOTCH3 双等位基因突变的临床和神经影像学特征。
Clinical and neuroradiological spectrum of biallelic variants in NOTCH3.
机构信息
Department of Neurogenetics, UCL Institute of Neurology London Queen Square and National Hospital for Neurology and Neurosurgery, University College London, London, United Kingdom; Department of Neurology, Donostia University Hospital, Biogipuzkoa Health Research Institute, Donostia-San Sebastián, Spain; CIBERNED, Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas-Instituto de Salud Carlos III (CIBER-CIBERNED-ISCIII), 28029, Madrid, Spain.
Neuroradiology Division, Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Division of Neuroradiology, Department of Radiology, Children's Hospital of Philadelphia, 3401 Civic Center Blvd., Philadelphia, PA, 19104, USA.
出版信息
EBioMedicine. 2024 Sep;107:105297. doi: 10.1016/j.ebiom.2024.105297. Epub 2024 Aug 26.
BACKGROUND
NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised.
METHODS
In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants.
FINDINGS
Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches.
INTERPRETATION
We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD.
FUNDING
The Wellcome Trust, the MRC.
背景
NOTCH3 编码一种对血管平滑肌细胞功能至关重要的跨膜受体。NOTCH3 变体是遗传性脑小血管病（SVD）的主要原因。虽然 NOTCH3 中的单等位基因胱氨酸涉及的错义变体在伴有皮质下梗死和白质脑病的常染色体显性脑动脉病（CADASIL）中得到了很好的研究，但 NOTCH3 中的双等位基因变体患者极为罕见，且特征描述不佳。
方法
在本研究中，我们提供了 25 例双等位基因 NOTCH3 变体患者的临床和遗传数据，并对另外 25 例病例（共 50 例患者）进行了文献复习。通过专家神经放射学家分析脑磁共振成像（MRI），以更好地了解与双等位基因 NOTCH3 变体相关的表型。
结果
我们的系统分析验证了 NOTCH3 中两种双等位基因变体的明确基因型-表型相关性。双等位基因失活变体（26 例）导致以痉挛、儿童期起病的中风和类似于脑室周围白质软化的围绕前房的白质体积丢失为特征的神经发育障碍。相反，双等位基因胱氨酸涉及的错义变体患者（24 例）属于 CADASIL 谱表型，具有成年早期起病的中风、痴呆和无明显体积丢失的深部白质病变。双等位基因胱氨酸涉及的错义变体患者的白质病变体积与 CADASIL 个体相当。值得注意的是，失活变体的单等位基因携带者主要无症状，只有少数病例报告非特异性头痛。
解释
我们根据剂量和变体类型提出了 NOTCH3-SVD 分类。本研究不仅扩展了我们对双等位基因 NOTCH3 变体的认识，还深入了解了疾病的潜在机制，有助于更全面地理解 NOTCH3 相关的 SVD。
资助
惠康信托基金会、MRC。
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