Back to Search
Start Over
Distinct neurological phenotypes associated with biallelic loss of NOTCH3 function: evidence for recessive inheritance.
- Source :
-
Molecular biology reports [Mol Biol Rep] 2024 Jun 01; Vol. 51 (1), pp. 714. Date of Electronic Publication: 2024 Jun 01. - Publication Year :
- 2024
-
Abstract
- Background: 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.<br />Methods and Results: 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.<br />Conclusion: 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.<br /> (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)
- Subjects :
- Humans
Male
Female
Adult
Genetic Association Studies
CADASIL genetics
Magnetic Resonance Imaging methods
Alleles
Homozygote
Consanguinity
Loss of Function Mutation genetics
Mutation genetics
Heterozygote
Receptor, Notch3 genetics
Pedigree
Exome Sequencing methods
Phenotype
Genes, Recessive genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1573-4978
- Volume :
- 51
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular biology reports
- Publication Type :
- Academic Journal
- Accession number :
- 38824264
- Full Text :
- https://doi.org/10.1007/s11033-024-09560-z