In particular, despite the shortcoming of a low number of patients analyzed, our identification of NOTCH3 and PTEN variants in CCM cases raises the possibility that the somatic mosaicism of either NOTCH3 or PTEN mutations and their impact on redox mechanisms and oxy-inflammatory responses contribute to CCM disease pathogenesis and severity, thereby supporting the necessity for implemented NGS analysis to enable the sensitive identification of causal genetic variants and effective polygenic risk prediction. The gene discussed is NOTCH3; the disease is cerebral cavernous malformation.