Sikta Neblina, Gooley Samuel, Green Timothy E, Hoeper Olivia, Witkowski Tom, Bennett Caitlin, Francis David, Reid Joshua, Mao Kevin, Awad Mohammed, Roberts-Thomson Samuel, Bulluss Kristian, Clark Jonathan, Scheffer Ingrid E, Perucca Piero, Bennett Mark F, Bahlo Melanie, Berkovic Samuel F, Hildebrand Michael S
Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, 245 Burgundy St, Heidelberg, VIC 3084, Australia.
Bladin-Berkovic Comprehensive Epilepsy Program, Department of Neurology, Austin Health, 145 Studley Rd, Heidelberg, VIC 3084, Australia.
Hum Mol Genet. 2025 Jul 20;34(15):1286-1293. doi: 10.1093/hmg/ddaf077.
Cerebral cavernous malformations (CCMs) are intracranial vascular lesions associated with risk of haemorrhages and seizures. While the majority are sporadic and often associated with somatic variants in PIK3CA and MAP3K3, around 20% are familial with germline variants in one of three CCM genes-KRIT1/CCM1, CCM2 and PDCD10/CCM3. We performed comprehensive phenotyping and genetic analysis of nine multiplex families and ten sporadic individuals with CCM. In the familial cases, initial standard analyses had a low yield, we therefore searched for small copy number changes and deep intronic variants. Subsequently, pathogenic germline variants in KRIT1/CCM1 or CCM2 were identified in all 9 multiplex families. Single or multiple exon deletions or splice site variants in KRIT1/CCM1 were found in 3/9 families. Where cavernous malformation tissue was available, second hit somatic PIK3CA variants were identified in 4/7 individuals. These 4 individuals were from separate families with germline KRIT1/CCM1 variants. In 8/10 sporadic cases, we detected recurrent pathogenic somatic PIK3CA, MAP3K3 or CCM2 variants. All familial cases had multiple CCMs, whereas the sporadic cases had a single lesion only, which was in the temporal lobe in 9/10 individuals. Our comprehensive approach interrogating deep intronic variants combined with detection of small copy number variants warrants implementation in standard clinical genetic testing pipelines to increase diagnostic yield. We also build on the established second hit germline and somatic variant mechanism in some CCM lesions. Genetic diagnosis has clinical implications such as reproductive counselling and provides potential eligibility for precision medicine therapies to treat rapidly growing CCMs.
脑海绵状血管畸形（CCM）是与出血和癫痫风险相关的颅内血管病变。虽然大多数是散发性的，且常与PIK3CA和MAP3K3中的体细胞变异相关，但约20%是家族性的，在三个CCM基因之一——KRIT1/CCM1、CCM2和PDCD10/CCM3中存在种系变异。我们对9个多重家庭和10名患有CCM的散发性个体进行了全面的表型分析和基因分析。在家族性病例中，最初的标准分析检出率较低，因此我们搜索了小拷贝数变化和内含子深处的变异。随后，在所有9个多重家庭中均鉴定出KRIT1/CCM1或CCM2中的致病性种系变异。在3/9的家庭中发现了KRIT1/CCM1中的单个或多个外显子缺失或剪接位点变异。在有海绵状血管畸形组织的情况下，在4/7的个体中鉴定出了第二次打击的体细胞PIK3CA变异。这4名个体来自不同的家族，带有种系KRIT1/CCM1变异。在8/10的散发性病例中，我们检测到复发性致病性体细胞PIK3CA、MAP3K3或CCM2变异。所有家族性病例都有多个CCM，而散发性病例只有单个病变，其中9/10的个体位于颞叶。我们对内含子深处变异进行检测并结合小拷贝数变异检测的综合方法，值得在标准临床基因检测流程中实施，以提高诊断检出率。我们还基于一些CCM病变中已确立的第二次打击种系和体细胞变异机制。基因诊断具有临床意义，如生殖咨询，并为治疗快速生长的CCM的精准医学疗法提供了潜在的适用条件。
