Distinct neurological phenotypes associated with biallelic loss of NOTCH3 function: evidence for recessive inheritance.
Humans
Receptor, Notch3
/ genetics
Male
Female
Pedigree
Exome Sequencing
/ methods
Phenotype
Genes, Recessive
/ genetics
Adult
Genetic Association Studies
CADASIL
/ genetics
Magnetic Resonance Imaging
/ methods
Alleles
Homozygote
Consanguinity
Loss of Function Mutation
/ genetics
Mutation
/ genetics
Heterozygote
CADASIL
Exome sequencing
Inheritance pattern
Leukodystrophy
Receptor, Notch3
Journal
Molecular biology reports
ISSN: 1573-4978
Titre abrégé: Mol Biol Rep
Pays: Netherlands
ID NLM: 0403234
Informations de publication
Date de publication:
01 Jun 2024
01 Jun 2024
Historique:
received:
26
01
2024
accepted:
16
04
2024
medline:
2
6
2024
pubmed:
2
6
2024
entrez:
1
6
2024
Statut:
epublish
Résumé
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.
Sections du résumé
BACKGROUND
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 AND RESULTS
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.
CONCLUSION
CONCLUSIONS
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.
Identifiants
pubmed: 38824264
doi: 10.1007/s11033-024-09560-z
pii: 10.1007/s11033-024-09560-z
doi:
Substances chimiques
Receptor, Notch3
0
NOTCH3 protein, human
0
Types de publication
Journal Article
Case Reports
Langues
eng
Sous-ensembles de citation
IM
Pagination
714Subventions
Organisme : National Institute for Medical Research Development
ID : 983886
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Nature B.V.
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