NOTCH3 Variants in Patients with Suspected CADASIL

Abstract

Background: Cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) is the most common hereditary form of cerebral small vessel disease. It is clinically, radiologically, and genetically heterogeneous and is caused by NOTCH3 mutations. Methods: In this study, we analyzed NOTCH3 in 368 patients with suspected CADASIL using next-generation sequencing. The significant variants detected were reported along with the clinical and radiological features of the patients. Results: Heterozygous NOTCH3 changes, mostly missense mutations, were detected in 44 of the 368 patients (~12%). Conclusions: In this single-center study conducted on a large patient group, 30 different variants were detected, 17 of which were novel. CADASIL, which can result in mortality, has a heterogeneous phenotype among individuals in terms of clinical, demographic, and radiological findings regardless of the NOTCH3 variant.

Membranous aplasia cutis congenita: A rare case report highlighting clinical presentation, genetic insights, and the need for comprehensive evaluation

“…Moreover, NOTCH3 is also expressed in hematopoietic progenitors and can partially substitute for NOTCH1 in T cell lineage specification [ 22 ]. The Notch signaling pathway plays a crucial role in regulating cardiovascular development and homeostasis [ 23 ], with NOTCH3 gene variants known to cause cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) [ 24 , 25 ]. Nonetheless, further research is warranted to elucidate the specific role of NOTCH3 variants in MACC and to determine any potential overlap with NOTCH1 -related mechanisms.…”

Most common NOTCH3 mutations causing CADASIL or CADASIL-like cerebral small vessel disease: A systematic review

“…1 Migraine is typically the first symptom associated with CADASIL, occurring at a mean age of 29 (±13.1), followed by depression and encephalopathy at a mean age of 41 (±10.2) [ 8 , 9 ]. Diagnosis of CADASIL occurs at a mean age of 57.8 (±14.7), with the onset of stroke/transient ischaemic attack (TIA) at a mean age of 47 (±9.5), dementia at a mean age of 54.6 (±9.7), and motor disability (MD) at a mean age of 60.5 (±2.5) [ 10 , 11 ]. Data derived from several references [ 1 , 2 , 13 , 46 , 60 ].…”