- •Homozygous mutations are extremely rare in CADASIL.
- •We report the largest series to date on NOTCH3 homozygous mutation and compare the phenotype to heterozygous patients.
- •Homozygous C3769T mutation was found in 7 family members, while heterozygous mutation was found in 6 members.
- •The phenotype of homozygous individuals is within the spectrum of CADASIL, although slightly at the severe end when compared to heterozygotes.
- •Genetic modifiers and environmental factors may play a role in the severity of the clinical phenotype and imaging features of CADASIL patients.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary microangiopathy caused by mutations in NOTCH3, very rarely homoallelic.
To describe the clinical, radiological, and neuropsychological features in an extended CADASIL family including members with either a homozygous or heterozygous NOTCH3 R1231C mutation.
The pedigree included 3 generations of a family with 13 affected individuals. The patients were examined clinically and radiologically. Neuropsychological testing was performed on the proband. Sequencing of the entire coding DNA sequence (CDS) and flanking regions of NOTCH3 was undertaken using PCR amplification and direct Sanger sequencing.
Homozygous C3769T mutation, predicting R1231C in exon 22 of NOTCH3 was found in 7 family members. Six other family members harbored the same in the heterozygous state. Homozygous individuals showed a slightly more severe clinical and radiological phenotype of earlier onset compared to their heterozygous counterparts.
This study reports the largest number of patients with homozygous NOTCH3 mutation. The phenotype and imaging features of homozygous individuals is within the spectrum of CADASIL, although slightly at the severe end when compared to heterozygotes carrying the same mutation. Both genetic modifiers and environmental factors may play an essential role in modification and alteration of the clinical phenotype and white matter changes among CADASIL patients.
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Published online: June 01, 2016
Accepted: May 31, 2016
Received in revised form: May 10, 2016
Received: September 22, 2015
© 2016 Elsevier B.V. All rights reserved.