Comprehensive analysis of Novel mutations in CCM1/KRIT1 and CCM2/ MGC4607 and their clinical implications in Cerebral Cavernous malformations

Background: Cerebral Cavernous Malformations (CCM) is a genetic disease characterized by vascular abnormalities in the brain and spinal cord, affecting 0.4-0.5 % of the population. We identified two novel pathogenic mutations, CCM1/KRIT1 c.811delT (p.Trp271GlyfsTer5) and CCM2/MGC4607 c.613_614insGG p.Glu205GlyfsTer31), which disrupt crucial protein domains and potentially alter disease progression. Objective: The study aims to comprehensively analyze a Brazilian cohort of CCM patients, integrating genetic, clinical, and structural aspects. Specifically, we sought to identify novel mutations within the CCM complex, and explore their potential impact on disease progression. Methods: We conducted a detailed examination of neuroradiological and clinical features in both symptomatic and asymptomatic CCM patients, performing genetic analyses through sequencing of the CCM1/KRIT1, CCM2/ MGC4607, , and CCM3/PDCD10 genes In silico structural predictions were carried out using PolyPhen-2, SIFT, and Human Genomics Community tools. Protein-protein interactions and docking analyses were explored using the STRING database. Results: Genetic analysis identifies 6 pathogenic mutations, 4 likely pathogenic, 1 variants of uncertain significance, and 7 unclassified mutations, including the novel mutations in CCM1 c.811delT and CCM2 c.613_614insGG. In silico structural analysis revealed significant alterations in protein structure, supporting their pathogenicity. Protein-protein interaction analysis indicated nuanced impacts on cellular processes. Clinically, we observed a broad spectrum of symptoms, including seizures and focal neurological deficits. However, no statistically significant differences were found in lesion burden, age of first symptom onset, or sex between the identified CCM1/KRIT1 and CCM2/MGC4607 mutations among all patients studied. Conclusion: This study enhances the understanding of CCM by linking clinical variability, genetic mutations, and structural effects. The identification of these novel mutations opens new avenues for research and potential therapeutic strategies.