Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy revisited: Genotype-phenotype correlations of all published cases

Abstract

Objective: The aim of this study was to evaluate the correlation between the various NOTCH3 mutations and their clinical and genetic profile, along with the presentation of a novel mutation in a patient.

Methods: Here, we describe the phenotype of a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) harboring a novel mutation. We also performed an extensive literature research for NOTCH3 mutations published since the identification of the gene and performed a systematic review of all published cases with NOTCH3 mutations. We evaluated the mutation pathogenicity in a great number of patients with detailed clinical and genetic evaluation and investigated the possible phenotype-genotype correlations.

Results: Our patient harbored a novel mutation in the NOTCH3 gene, the c.3084 G > C, corresponding to the aminoacidic substitution p.Trp1028Cys, presenting with seizures as the first neurologic manifestation. We managed to find a correlation between the pathogenicity of mutations, severity of the phenotype, and age at onset of CADASIL. Significant differences were also identified between men and women regarding the phenotype severity.

Conclusions: The collection and analysis of these scarce data published since the identification of NOTCH3 qualitatively by means of a systematic review and quantitatively regarding genetic profile and pathogenicity scores, highlight the significance of the ongoing trend of investigating phenotypic genotypic correlations.

Figure 1. Brain MRI scan (A–C) of the patient showing extensive leukoencephalopathy, mainly in the frontal lobes, the anterior temporal lobe, the external capsules, and the basal ganglia in the FLAIR sequences (D–F) of the daughter showing multiple hyperintensities in the FLAIR sequences

Figure 2. Flow chart depicting our literature search and study selection for the systematic review

Figure 3. A world map showing the frequencies of CADASIL mutations across various countries according to our reviewed cases

Figure 4. The distribution of the most common mutations across the NOTCH3 gene

Figure 5. Univariate analysis showing the effect of pathogenicity score of the mutations on the age at onset of the disorder

Figure 6. Bar chart showing the differences between men and women regarding phenotype severity

Phenotype severity-sex, p value = 0.003.

Figure 7. Box plot depicting the distribution of phenotypes of CADASIL across age

Phenotype severity-age, p < 0.001.

Figure 8. Bar chart showing the distribution of mutations across the exons of the gene according to their pathogenicity score

Εxon-pathogenicity score, p value< 0.001.