Exome-based gene panel analysis in a cohort of acute juvenile ischemic stroke patients:relevance of NOTCH3 and GLA variants

Abstract

Background Genetic variants are considered to have a crucial impact on the occurrence of ischemic stroke. In clinical routine, the diagnostic value of next-generation sequencing (NGS) in the medical clarification of acute juvenile stroke has not been investigated so far. Material and methods We analyzed an exome-based gene panel of 349 genes in 172 clinically well-characterized patients with magnetic resonance imaging (MRI)-proven, juvenile (age ≤ 55 years), ischemic stroke admitted to a single comprehensive stroke center. Results Monogenetic diseases causing ischemic stroke were observed in five patients (2.9%): In three patients with lacunar stroke (1.7%), we identified pathogenic variants in NOTCH3 causing cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Hence, CADASIL was identified at a frequency of 12.5% in the lacunar stroke subgroup. Further, in two male patients (1.2%) suffering from lacunar and cardioembolic stroke, pathogenic variants in GLA causing Fabry’s disease were present. Additionally, genetic variants in monogenetic diseases lacking impact on stroke occurrence, variants of unclear significance (VUS) in monogenetic diseases, and (cardiovascular-) risk genes in ischemic stroke were observed in a total of 15 patients (15.7%). Conclusion Genetic screening for Fabry’s disease in cardioembolic and lacunar stroke as well as CADASIL in lacunar stroke might be beneficial in routine medical work-up of acute juvenile ischemic stroke.

Cerebrovascular disorders and Fabry disease

“…Among the 5 males with pathogenic variants, 3 exhibited the Type 1 phenotype while 2 displayed the Type 2 phenotype. Similarly, a prevalence of 1.11% of patients with FD was found in females (n = 23), but when the benign variants were excluded, only 3 presented pathogenic variants with the Type 1 phenotype and the actual prevalence dropped to 0.14%, similar to that in males [76] . The authors found that most FD patients identified in stroke clinics had the Classic phenotype and, therefore, should have been diagnosed earlier by their pediatricians and family doctors [76] .…”

“…In recent years, significant improvement was made in the genotype-phenotype correlation of young patients with stroke included in screening studies of FD, and as a consequence, a lower prevalence of 0.1%-0.3% was estimated [75,76] . This prevalence may be higher in young patients with either cryptogenic or recurrent stroke [75] .…”

Impact of GLA Variant Classification on the Estimated Prevalence of Fabry Disease: A Systematic Review and Meta-Analysis of Screening Studies

“…Among the 3941 studies identified from the initial database search, 110 met the inclusion criteria and were analyzed for the systematic review and meta-analysis (Figure 1; Table SI). Among the included studies, 26 reports screened patients with left ventricular hypertrophy (LVH)/hypertrophic cardiomyopathy (HCM), 12–37 38 patients with end-stage renal disease (ESRD)/chronic kidney disease (CKD), 38–74 25 patients with stroke patients, 75–99 15 patients with newborns, 100–114 3 patients with small-fiber neuropathy patients, 115–117 and 3 patients with atrioventricular block or sinus node dysfunction requiring pacemaker implantation 118–120 (Figure 2).…”

“…Twenty-five studies performing screening in patients with stroke met the inclusion criteria, 75–99 providing data on the prevalence of FD among 15 295 patients screened.…”

Pro‐Hemorrhagic Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Associated with NOTCH3 p.R75P Mutation with Low Vascular NOTCH3 Aggregation Property

“…21 The NOTCH3 p.R75P mutation has been identified in patients with CADASIL in South Korea and China, but not in non-East Asian people, such as British, French, Finnish, Swedish, German, and Brazilian, indicating that different NOTCH3 mutations are associated with distinct CADASIL phenotypes between East Asian and white European populations. 17,18,[22][23][24][25][26] Additionally, the cysteine-altering NOTCH3 p.R544C mutation was evaluated for its association with ICH, because it is an East Asian-specific mutation, but the result was negative. 6 Intriguingly, the first report of the NOTCH3 p.R75P mutation from South Korea showed a high frequency of this mutation among CADASIL patients with CMB.…”