Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Department of Pediatrics, Division of Pediatric Neurology, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
Mol Biol Rep. 2024 Jun 1;51(1):714. doi: 10.1007/s11033-024-09560-z.
NOTCH3 variants are known to be linked to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, some null NOTCH3 variants with homozygous inheritance cause neurological symptoms distinct from CADASIL. The aim of this study was to expand the clinical spectrum of this distinct condition and provide further evidence of its autosomal recessive inheritance.
Whole exome sequencing (WES) was performed on a proband who exhibited livedo racemosa, ataxia, cognitive decline, seizures, and MRI white matter abnormalities without anterior temporal pole lesions. Segregation analysis was conducted with Sanger sequencing. WES of the proband identified a novel homozygous NOTCH3 null variant (c.2984delC). The consanguineous parents were confirmed as heterozygous variant carriers. In addition, three heterozygous NOTCH3 null variants were reported as incidental findings in three unrelated cases analyzed in our center.
The findings of this study suggest an autosomal recessive inheritance pattern in this early-onset leukoencephalopathy, in contrast to CADASIL's dominant gain-of-function mechanism; which is a clear example of genotype-phenotype correlation. Comprehensive genetic analysis provides valuable insights into disease mechanisms and facilitates diagnosis and family planning for NOTCH3-associated neurological disorders.
已知 NOTCH3 变异与伴有皮质下梗死和白质脑病的常染色体显性脑动脉病（CADASIL）有关。然而，一些具有纯合遗传的无功能 NOTCH3 变异会引起与 CADASIL 不同的神经症状。本研究旨在扩展这种特殊疾病的临床谱，并提供其常染色体隐性遗传的进一步证据。
对表现出 Racemosa 皮肤斑、共济失调、认知能力下降、癫痫发作和 MRI 白质异常但无前颞极病变的先证者进行了全外显子组测序（WES）。采用 Sanger 测序进行分离分析。先证者的 WES 发现了一种新的纯合无功能 NOTCH3 变异（c.2984delC）。同系父母被确认为杂合变异携带者。此外，在我们中心分析的三个无关病例中，还报告了三个杂合无功能 NOTCH3 变异作为偶然发现。
本研究的发现提示这种早发性白质脑病呈常染色体隐性遗传模式，与 CADASIL 的显性获得性功能机制相反；这是基因型-表型相关性的一个明确例证。全面的遗传分析为疾病机制提供了有价值的见解，并有助于 NOTCH3 相关神经障碍的诊断和家庭规划。
