Abstract
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.
Highlights
Cerebral cavernous malformation (CCM, OMIM 116860) is a vascular malformation characterized by clustered enlarged capillary-like channels and the absence of the intervening neural tissue
Of the 95 patients, 15 (15.8%) had a relevant family history and the remaining 80 (84.2%) had a sporadic onset. 92 patients (96.8%) had multiple cerebral lesions and only 3 (3.2%) had a single lesion in their brain
The most common initial presentation was focal neurological signs (54 patients, 56.8%), including weakness, numbness, diplopia, and dysarthria, followed by seizure (28 patients, 29.5%; 3.2% with concurrent focal neurological signs) and headache (21 patients, 22.1%; 13.7% with concurrent focal neurological signs or seizure); only eight patients (8.4%) were asymptomatic
Summary
Cerebral cavernous malformation (CCM, OMIM 116860) is a vascular malformation characterized by clustered enlarged capillary-like channels and the absence of the intervening neural tissue. CCM can be sporadic or familial, and familial cases usually have multiple lesions[2]. The symptoms of CCM include hemorrhage-related focal neurological deficits, seizure, and headache; patients with CCM are usually asymptomatic[1]. Multiple pathogenic variants have been reported in these genes, and several studies have been conducted in ethnically Chinese populations[6–19], with only one case reported in Taiwan[20]. We retrospectively collected clinical and magnetic resonance imaging (MRI) data of patients who had received a diagnosis of CCM on the basis of brain MRI findings from 1998 to 2006 in a tertiary medical center. Thereafter, we performed DNA analysis to identify variants in patients with multiple lesions or with relevant family histories. We aimed to establish an epidemiological and clinical data bank and identify CCM pathological variants in an ethnic Chinese population in Taiwan. Male Female Yes No Hypertension Heart disease Diabetes mellitus Coagulopathy Malignancy Multiple Single Supra-tentorial Extra-cranial Infra-tentorial Concurrent Focal neurological signs Weakness Vertigo Diplopia Numbness Tinnitus Dysarthria Gait disturbance Facial palsy Visual field defect Seizure Alone With focal signs Headache Alone With focal signs With seizure Incidental finding Surgical removal Radiotherapy Done Not done
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