家族性脑海绵状畸形(FCCMs)主要通过经典CCM基因突变遗传,包括CCM1/KRIT1、CCM2/MGC4607和CCM3/PDCD10。FCCM可引起严重的临床症状,包括癫痫发作,颅内出血(ICH),或功能性神经缺陷(FND)。在这项研究中,我们报道了一个中国家庭中KRIT1的新突变,并伴有NOTCH3突变。这个家庭由8名成员组成,其中4人使用脑MRI诊断为CCM(T1WI,T2WI,SWI)。先证者(II-2)及其女儿(III-4)患有脑出血和难治性癫痫,分别。基于4例多个CCM患者和2例正常一级亲属的全外显子组测序(WES)数据和生物信息学分析,一个新的KRIT1突变,NG_012964.1(NM_194456.1):c.1255-1G>T(splice-3),内含子13被认为是该家族的致病基因。此外,基于2名严重和2名轻度CCM患者,我们发现了SNV错义突变,NG_009819.1(NM_000435.2):c.1630C>T(p。R544C),在NOTCH3。最后,使用Sanger测序在8名成员中验证了KRIT1和NOTCH3突变.这项研究揭示了一个新的KRIT1突变,NG_012964.1(NM_194456.1):c.1255-1G>T(splice-3),在一个中国的CCM家族里,以前没有报道过。此外,NOTCH3突变NG_009819.1(NM_000435.2):c.1630C>T(p.R544C)可能是第二次打击,并与CCM病变的进展和严重的临床症状有关。
Family cerebral cavernous malformations (FCCMs) are mainly inherited through the mutation of classical CCM genes, including CCM1/
KRIT1, CCM2/MGC4607, and CCM3/PDCD10. FCCMs can cause severe clinical symptoms, including epileptic seizures, intracranial hemorrhage (ICH), or functional neurological deficits (FNDs). In this study, we reported a novel mutation in
KRIT1 accompanied by a NOTCH3 mutation in a Chinese family. This family consists of 8 members, 4 of whom had been diagnosed with CCMs using cerebral MRI (T1WI, T2WI, SWI). The proband (II-2) and her daughter (III-4) had intracerebral hemorrhage and refractory epilepsy, respectively. Based on whole-exome sequencing (WES) data and bioinformatics analysis from 4 patients with multiple CCMs and 2 normal first-degree relatives, a novel
KRIT1 mutation, NG_012964.1 (NM_194456.1): c.1255-1G > T (splice-3), in intron 13 was considered a pathogenic gene in this family. Furthermore, based on 2 severe and 2 mild CCM patients, we found an SNV missense mutation, NG_009819.1 (NM_000435.2): c.1630C > T (p.R544C), in NOTCH3. Finally, the
KRIT1 and NOTCH3 mutations were validated in 8 members using Sanger sequencing. This study revealed a novel
KRIT1 mutation, NG_012964.1 (NM_194456.1): c.1255-1G > T (splice-3), in a Chinese CCM family, which had not been reported previously. Moreover, the NOTCH3 mutation NG_009819.1 (NM_000435.2): c.1630C > T (p.R544C) might be a second hit and associated with the progression of CCM lesions and severe clinical symptoms.