Small Vessel Disease Phenotype Associated With Monoallelic <i>NOTCH3</i> Loss-of-Function Variants.

Abstract

Monoallelic cysteine-altering <i>NOTCH3</i> (<i>NOTCH3</i>^<i>cys</i>) variants cause the adult-onset small vessel disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and biallelic <i>NOTCH3</i> loss-of-function (<i>NOTCH3</i>^<i>lof</i>) variants cause a rare, childhood-onset small vessel disease. Whether monoallelic <i>NOTCH3</i>^<i>lof</i> variants also cause a small vessel disease is subject of debate. The aim of this study was to delineate the small vessel disease phenotype of individuals with a monoallelic <i>NOTCH3</i>^<i>lof</i> variant and to compare it with CADASIL. In this observational study, monoallelic <i>NOTCH3</i>^<i>lof</i> cases were ascertained in Genome Aggregation Database (gnomAD); UK Biobank; 6 clinical centers from Europe, Asia, and the United States; and literature. In gnomAD, <i>NOTCH3</i>^<i>lof</i> allele frequency was determined. In UK Biobank, normalized white matter hyperintensity volume (nWMHv), peak width of skeletonized mean diffusivity (PSMD), lacune count, and stroke were compared among <i>NOTCH3</i>^<i>lof</i> cases, <i>NOTCH3</i>^<i>cys</i> cases, and controls. In clinical <i>NOTCH3</i>^<i>lof</i> cases, white matter hyperintensities, lacune count, and stroke incidence were assessed, and skin vessel wall pathology was analyzed using immunohistochemistry and electron microscopy. In gnomAD, 306 <i>NOTCH3</i>^<i>lof</i> variants were identified (allele frequency 0.6/1,000). In UK Biobank, 102 <i>NOTCH3</i>^<i>lof</i> cases were ascertained (median age 58 years, range 40-69, 55% female). <i>NOTCH3</i>^<i>lof</i> cases had an increased nWMHv (Δ0.44 mm³, <i>p</i> < 0.001) and PSMD (Δ0.19 × 10^-4, <i>p</i> = 0.017) compared with controls. nWMHv and PSMD in <i>NOTCH3</i>^<i>lof</i> cases were comparable to <i>NOTCH3</i>^<i>cys</i> cases; however, in contrast to <i>NOTCH3</i>^<i>cys</i> cases, <i>NOTCH3</i>^<i>lof</i> cases did not have an increased stroke risk compared with controls. Clinically ascertained <i>NOTCH3</i>^<i>lof</i> cases (n = 69, median age 50 years, range 20-94, 54% female) often had white matter hyperintensities (28/32, 88%) while lacunes (12/32, 38%) and stroke (11/69, 15%) were predominantly seen in cases with cardiovascular risk factors and at advanced age. Skin vessels of <i>NOTCH3</i>^<i>lof</i> cases more frequently showed abundant vessel wall collagen deposition compared with <i>NOTCH3</i>^<i>cys</i> cases and controls (37% vs 10% [<i>p</i> = 0.016] and 5% [<i>p</i> < 0.001] of vessels). We conclude that monoallelic <i>NOTCH3</i>^<i>lof</i> variants cause a small vessel disease that (1) remains subclinical in most cases but may be exacerbated by cardiovascular risk factors and aging, and (2) is distinct from CADASIL regarding vessel pathology and disease severity. These findings will guide counseling and management of individuals in whom a <i>NOTCH3</i>^<i>lof</i> variant is found.