Related Experiment Video

Updated: Apr 9, 2026

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
09:34

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease

Published on: April 4, 2018

35.0K

An in trans NOTCH3 loss-of-function variant modifies disease severity in CADASIL: A family-based study

Shih-Chun Lan1,2, Yi-Hong Liu1,3, Jui Lan4

  • 1Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.

Journal of the Chinese Medical Association : JCMA
|April 8, 2026
PubMed

Insights

Reduced NOTCH3 gene dosage may influence the severity of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This study highlights intrafamilial phenotypic heterogeneity in a family with NOTCH3 variants.

Area of Science:

  • Genetics
  • Neurology
  • Molecular Biology

Background:

  • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disorder caused by NOTCH3 gene variants.
  • Disease severity in CADASIL shows significant variation, and the effect of reduced NOTCH3 gene dosage is not fully understood.

Purpose of the Study:

  • To investigate the impact of reduced NOTCH3 gene dosage on CADASIL severity.
  • To analyze a family with diverse NOTCH3 variants and intrafamilial phenotypic heterogeneity.

Main Methods:

  • Clinical assessment, brain MRI, and genetic analysis were performed on four related individuals.
  • NOTCH3 complementary DNA (cDNA) sequencing and skin biopsy were utilized to assess gene expression and protein presence.

Main Results:

  • A proband with compound heterozygous NOTCH3 variants (cysteine-altering and loss-of-function) presented with severe CADASIL symptoms and extensive brain imaging abnormalities.
  • Individuals carrying a single NOTCH3 variant (either cysteine-altering or loss-of-function) exhibited milder clinical and imaging phenotypes.
  • Reduced loss-of-function allele expression was observed in skin tissue, and NOTCH3 extracellular domain immunoreactivity was present only in carriers of the cysteine-altering variant.

Conclusions:

  • Reduced NOTCH3 gene dosage appears to be a modifying factor in CADASIL disease severity.
  • Intrafamilial phenotypic heterogeneity in CADASIL can be influenced by the specific combination and dosage of NOTCH3 variants.
Abstract

Keywords:
CADASILLoF variantLoss-of-function variant

More Related Videos

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila06:41

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila

Published on: August 20, 2019

14.5K
Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information09:37

Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information

Published on: August 15, 2019

10.6K

Related Concept Videos

Notch Signaling Pathway03:14

Notch Signaling Pathway

The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
6.9K
Notch Signaling Pathway03:14

Notch Signaling Pathway

6.5K
Role Of Notch Signalling In Intestinal Stem Cell Renewal01:12

Role Of Notch Signalling In Intestinal Stem Cell Renewal

Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
2.6K
Cystic Fibrosis: Pathogenesis01:23

Cystic Fibrosis: Pathogenesis

Cystic fibrosis (CF), an autosomal recessive disorder, significantly affects the function of exocrine glands. This genetically inherited disease is characterized by the production of thick and sticky mucus, which can severely affect various organs and systems in the body.
CF is primarily caused by a genetic mutation in a chromosome 7 gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common gene mutation leading to CF is the ΔF508 mutation,...
1.1K
Pharmacogenomics: Identification of New Drug Targets01:29

Pharmacogenomics: Identification of New Drug Targets

Advances in genomics have profoundly influenced drug discovery by increasing both the speed and accuracy of pharmaceutical development. Pharmacogenomics, which examines how genetic variation influences drug response, facilitates the identification of novel therapeutic targets and enables patient stratification for personalized treatment. These strategies contribute to improved drug efficacy, minimized adverse effects, and more efficient clinical trial design.Mapping genetic differences...
88
Cardiomyopathy III: Hypertrophic Cardiomyopathy01:29

Cardiomyopathy III: Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy, or HCM, is an autosomal dominant genetic disorder characterized by asymmetric left ventricular hypertrophy without ventricular dilation. It is more common in men and is typically diagnosed in young, athletic adults.EtiologyHCM is primarily genetic and is caused by mutations in genes encoding sarcomeric proteins. Researchers have identified over 1400 mutations across at least 11 different genes. Among these, the most frequently occurring mutations are found in the...
748