Distinct neurological phenotypes associated with biallelic loss of NOTCH3 function: evidence for recessive inheritance.
Mol Biol Rep
; 51(1): 714, 2024 Jun 01.
Article
em En
| MEDLINE
| ID: mdl-38824264
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. METHODS ANDRESULTS:
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.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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linhagem
/
Fenótipo
/
Receptor Notch3
/
Sequenciamento do Exoma
/
Genes Recessivos
Limite:
Adult
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Mol Biol Rep
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Irã