Abstract 196: Polymorphisms in Cerebral Cavernous Malformation Signaling Pathway Genes Associated With Severity of Cerebral Cavernous Malformation Type 1

Abstract

Objective: Familial cerebral cavernous malformation (CCM) is an autosomal dominant disease caused by mutations in CCM1 , CCM2 or CCM3 , and characterized by multiple brain lesions that can lead to intracerebral hemorrhage (ICH), seizures, and neurological deficits. Carriers of the same mutation can manifest variable symptoms and severity of disease, suggesting the influence of modifiers. As the three CCM proteins form a trimeric complex in vitro and interact with many other proteins, we hypothesized that variants in CCM1-2-3 and in other genes encoding proteins involved in CCM signaling modify disease severity, as manifested by ICH and greater total or large lesion counts. Methods: We analyzed 188 Hispanic CCM1 patients harboring the common Hispanic mutation (CHM, CCM1 Q455X). ICH and lesion counts at enrollment were obtained by clinical assessment and MRI. Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 504 variants (MAF≥1%) within +/- 5kb of 42 genes for association with ICH, total and large (≥5 mm in diameter) lesion counts, adjusting for age, gender and family structure. Results: At baseline, 30.3% of CCM1-CHM patients had a history of ICH. Mean total lesion count was 60.1 ± 115.0 (range 0 to 713). Mean large lesion count was 4.9 ± 8.7 (range 0 to 104). Two NTRK1 variants (rs41267423 and rs1800879) as well as SLMAP rs7621574 and PCDHGA1 rs17097189 were significantly associated with ICH ( P ≤0.014). Suggestive associations with ICH ( P ≤0.05) were observed for additional 15 variants in 11 genes. RAP1GAP rs2625408 was associated with both total and large lesion counts ( P ≤0.004) and additional 4 variants in 4 genes were associated with one of these phenotypes. No single variant was associated with both ICH and total or large lesion count; however, different variants in RAP1GAP and KDR genes were associated with all three phenotypes tested. Conclusions: Variants in genes involved in CCM signaling may contribute to variability in CCM1 disease severity. Genotypes that replicate in other cohorts might be useful as predictors in clinical management.