CCM1 and CCM2 variants in patients with cerebral cavernous malformation in an ethnically Chinese population in Taiwan

• Published in: Scientific reports 2019-08, Vol.9 (1), p.12387-9, Article 12387
• Main Authors: Chang, Chun-Wei, Hsu, Peng-Wei, Wei, Kuo-Chen, Chang, Chia-Wen, Fung, Hon-Chung, Hsih, Mo-Song, Hsu, Wen-Chuin, Ro, Long-Sun, Chang, Chen-Nen, Wang, Jiun-Jie, Wu, Yih-Ru, Chen, Sien-Tsong
• Format: Article
• Language: English
• Subjects: 38/23; 38/77; 631/208/2489; 692/617/375/1370; Adult; Apoptosis; Asian Continental Ancestry Group - genetics; Brain - diagnostic imaging; Carrier Proteins - genetics; CCM2 protein; Cell death; Central nervous system; Clonal deletion; Diplopia; DNA Mutational Analysis; Dysarthria; Exons; Family medical history; Female; Genes; Genomics; Headaches; Hemangioma, Cavernous, Central Nervous System - genetics; Hemangioma, Cavernous, Central Nervous System - pathology; Heterozygote; Hospitals; Humanities and Social Sciences; Humans; INDEL Mutation; Insertion; KRIT1 Protein - genetics; Magnetic Resonance Imaging; Male; Middle Aged; multidisciplinary; Mutation, Missense; Neurosurgery; Nucleotide sequence; Patients; Pedigree; Population; Radiation therapy; Retrospective Studies; RNA Splice Sites - genetics; Science; Science (multidisciplinary); Spinal cord; Taiwan
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-48448-y

Cerebral cavernous malformation (CCM) is a vascular malformation characterized by clustered enlarged capillary-like channels in the central nervous system. The genes harboring variants in patients with CCM include CCM1 /Krev interaction trapped-1, CCM2 /MGC4607, and CCM3 /programmed cell death protein 10. We aimed to identify pathogenic variants in an ethnic Chinese population in Taiwan. We recruited 95 patients with multiple CCMs or a single lesion with a relevant family history. Sanger sequencing was performed for 41 patients. Variants were identified using sequence alignment tools, and the clinical significance of these variants was determined using American College of Medical Genetics and Genomics standards and guidelines. Several pathogenic variants were found in six patients, including three unrelated patients and three affected members of one family. Two novel pathogenic variants leading to early truncation comprised a deletion variant in exon 18 of CCM1 (c.1846delA; p.Glu617LysfsTer44) and an insertion variant in exon 4 of CCM2 (c.401_402insGCCC; p.Ile136AlafsTer4). One novel pathogenic splice site variant was c.485 + 1G > C at the beginning of intron 8 of CCM1 . In this study, we identified novel variants related to CCM in an ethnically Chinese population in Taiwan.