Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank: CADASIL to nonpenetrance

Abstract

Objective: To determine the small vessel disease spectrum associated with cysteine-altering NOTCH3 variants in community-dwelling individuals by analyzing the clinical and neuroimaging features of UK Biobank participants harboring such variants.

Methods: The exome and genome sequencing datasets of the UK Biobank (n = 50,000) and cohorts of cognitively healthy elderly (n = 751) were queried for cysteine-altering NOTCH3 variants. Brain MRIs of individuals harboring such variants were scored according to Standards for Reporting Vascular Changes on Neuroimaging criteria, and clinical information was extracted with ICD-10 codes. Clinical and neuroimaging data were compared to age- and sex-matched UK Biobank controls and clinically diagnosed patients from the Dutch cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) registry.

Results: We identified 108 individuals harboring a cysteine-altering NOTCH3 variant (2.2 of 1,000), of whom 75% have a variant that has previously been reported in CADASIL pedigrees. Almost all variants were located in 1 of the NOTCH3 protein epidermal growth factor-like repeat domains 7 to 34. White matter hyperintensity lesion load was higher in individuals with NOTCH3 variants than in controls (p = 0.006) but lower than in patients with CADASIL with the same variants (p < 0.001). Almost half of the 24 individuals with brain MRI had a Fazekas score of 0 or 1 up to age 70 years. There was no increased risk of stroke.

Conclusions: Although community-dwelling individuals harboring a cysteine-altering NOTCH3 variant have a higher small vessel disease MRI burden than controls, almost half have no MRI abnormalities up to age 70 years. This shows that NOTCH3 cysteine altering variants are associated with an extremely broad phenotypic spectrum, ranging from CADASIL to nonpenetrance.

Figure 1. NOTCH3 variant position and stroke frequency in UKB compared to patients with CADASIL

(A) Schematic representation of the NOTCH3 protein and variant distribution in UK Biobank (UKB) vs cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). In CADASIL pedigrees, ≈70% of individuals have a cysteine-altering NOTCH3 variant in 1 of the epidermal growth factor–like repeat (EGFr) domains 1 to 6 and ≈30% in 1 of the EGFr domains 7 to 34. In the UKB, the vast majority of cysteine-altering NOTCH3 variants (97%) are located in EGFr 7 to 34. (B) Kaplan-Meier plot showing the difference in age at first stroke between individuals with a NOTCH3 EGFr 7 to 34 variant from UKB, patients with CADASIL with an EGFr 7 to 34 variant, and patients with CADASIL with an EGFr 1 to 6 variant, as determined in a previously published study in 251 individuals from the Dutch CADASIL registry. ECD = extracellular domain; ICD = intracellular domain; TM = transmembrane domain.

Figure 2. Neuroimaging in cases with a cysteine-altering NOTCH3 variant in UKB

(A) Brain MRI T2–fluid-attenuated inversion recovery (FLAIR) images of 4 representative cases with a cysteine-altering NOTCH3 variant in the UK Biobank (UKB). From left to right: a 50-year old woman with a normal brain MRI; a 52-year old woman with periventricular and subcortical white matter hyperintensities (WMH) (Fazekas deep white matter [DWM] score 2 and periventricular white matter [PVWM] score 3) and a lacune; a 70-year old man with only minimal WMH in the external capsules (Fazekas DWM score 1 and PVWM score 1); and a 72-year old man with subcortical and basal ganglia WMH (Fazekas DWM score 3 and PVWM score 3). (B) Brain MRI T2-FLAIR images of 4 representative cases with a cysteine altering NOTCH3 variant in epidermal growth factor–like repeat (EGFr) 7 to 34 from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) pedigrees. From left to right: a 50-year old woman with extensive WMH (Fazekas DWM score 3 and PVWM score 3); a 58-year old man with only minimal WMH (Fazekas DWM score 1 and PVWM score 1); a 68-year old woman with extensive WMH (Fazekas DWM score 3 and PVWM score 3) and lacunes; and a 77-year old woman with extensive WMH (Fazekas DWM score 3 and PVWM score 3) and lacunes. (C and D) Violin plots showing Fazekas DWM and PVWM scores of UKB controls, UKB^{NOTCH3 7-34} cases, and CADASIL^{NOTCH3 7-34} cases. WMH lesion load in UKB^{NOTCH3 7-34} cases was significantly lower than in CADASIL^{NOTCH3 7-34} cases but significantly higher than in UKB controls (for statistical analyses, see table 2). Almost half (10 of 24) of UKB^{NOTCH3 7-34} cases had a Fazekas score of 0 or 1 in both DWM and PVWM. In contrast, almost all (21 of 24) CADASIL^{NOTCH3 7-34} cases had a Fazekas score of ≥2 in both DWM and PVWM. (E) Bar charts showing the frequency of lacunes, microbleeds, and brain atrophy in UKB controls, UKB^{NOTCH3 7-34} cases, and CADASIL^{NOTCH3 7-34} cases. *A lacune.

Figure 3. Brain MRI in an 84-year-old cognitively healthy control from ADNI with a NOTCH3 p.Cys1222Gly variant

T2-weighted images showing subtle white matter hyperintensities, dilated perivascular spaces, and brain atrophy. ADNI = Alzheimer's Disease Neuroimaging Initiative.