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Distinct Neurological Phenotypes Associated With Biallelic Loss of Notch3 Function: Evidence for Recessive Inheritance Publisher Pubmed



Tasharrofi B1 ; Najafi A1 ; Pourbakhtyaran E2 ; Amirsalari S3 ; Khan GS2 ; Ashrafi MR2 ; Tavasoli AR4, 5 ; Keramatipour M6 ; Heidari M2, 5
Authors
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Authors Affiliations
  1. 1. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Department of Pediatrics, Division of Pediatric Neurology, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  3. 3. Pediatric Neurology Department, New Hearing Technologies Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
  4. 4. Department of Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, United States
  5. 5. Pediatric Neurology Division, Pediatrics Center of Excellence, Myelin Disorders Clinic, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  6. 6. Watson Genetic Laboratory, North Kargar Street, Tehran, Iran

Source: Molecular Biology Reports Published: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. 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. 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. © The Author(s), under exclusive licence to Springer Nature B.V. 2024.