Clinical Relevance of Genetic Variants in Juvenile Stroke Patients: A Plea for a Precise Classification

Abstract

With great interest, we read the research article by Park et al 1 reporting pathogenic or likely pathogenic variants according to American College of Medical Genetics and Genomics (ACMG) guidelines in 1 of 15 examined stroke genes in 12.7% of their Korean cohort of juvenile stroke. The authors classify them as "clinically relevant genetic variants" (CRGVs) but do not necessarily claim causality. In this context, we would like to discuss the clinical interpretation of genetic variants and the implementation of the umbrella term CRGV, with 3 considerations.First, Park et al describe heterozygous variants in CBS and ABCC6 as CRGVs. Whereas biallelic pathogenic variants account for autosomal recessive homocystinuria and pseudoxanthoma elasticum, monoallelic variants can represent risk alleles in ischemic stroke. 2 Such risk alleles in disease-causing genes are not necessarily causative, and the clinical impact on individuals is unclear. Beyond that, variant classification can lead to conflicting results in different sources; the variants c.*38G > A and c.1990C > T in ABCC6 are classified as pathogenic by Park et al, but mostly as likely benign on ClinVar (IDs 433370, 433252).Second, Park et al detect the p.Arg4810Lys variant in RNF213 in 5.7% of patients. RNF213 constitutes a susceptibility gene of moyamoya disease (MMD). The variant is currently not deemed to be causative of MMD, and European guidelines do not recommend testing in clinical routine. 3 Susceptibility genes should be differentiated from disease-causing genes, and application of ACMG guidelines is recommended for genes causing monogenic disorders only. 4 The authors nicely illustrate that only a quarter of patients with this variant show features of MMD and discuss an association of this variant with intracranial artery stenosis. They state that clinical implications of the variant have to be explored.Third, pathogenic variants in NOTCH3 are present in 15 of the Korean patients; however, 11 patients do not show imaging features of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and penetrance of the variants remains undetermined. Park et al highlight that NOTCH3 variants may have incomplete penetrance and therefore pathogenic variants may not be clinically relevant.Concluding, we would like to emphasize the benefits of a precise genetic classification, which differentiates highly penetrant pathogenic variants associated with monogenic diseases from variants that serve as risk alleles in both disease-causing and susceptibility genes. This is relevant not only in juvenile stroke but also in other neurological diseases with monogenic forms as well as genetic risk factors, for example, amyotrophic lateral sclerosis and Parkinson disease. Applying this classification in German juvenile ischemic stroke patients, we detected a monogenic disease in 2.9% (CADASIL, Fabry disease) and variants in genes associated with an increased risk of stroke in another 2.9% (RNF213, ABCC6, PROS1). 5