Prevalence, genetic and clinical characteristics in first-degree relatives of patients with familial cerebral cavernous malformations in China

Abstract

Objective: This study aims to investigate the prevalence of familial cerebral cavernous malformations (FCCMs) in first-degree relatives (FDRs) using familial screening, to describe the distribution of initial symptoms, lesion count on cranial MRI and pathogenic gene in patients.

Methods: Patients with multiple CCMs who enrolled from the Treatments and Outcomes of Untreated Cerebral Cavernous Malformations in China database were considered as probands and FDRs were recruited. Cranial MRI was performed to screen the CCMs lesions, and whole-exome sequencing was performed to identify CCM mutations. MRI and genetic screening were combined to diagnose FCCM in FDRs, and the results were presented as prevalence and 95% CIs. The Kaplan-Meier (KM) method was used to calculate the cumulative incidence of FCCM.

Results: 33 (76.74%) of the 43 families (110 FDRs) were identified as FCCM (85 FDRs). Receiver operating characteristic analysis revealed three lesions on T2-weighted imaging (T2WI) were the strong indicator for distinguishing probands with FCCM (sensitivity, 87.10%; specificity, 87.50%). Of the 85 FDRs, 31 were diagnosed with FCCM, resulting in a prevalence of 36.5% (26.2%-46.7%). In families with FCCMs, the mutation rates for CCM1, CCM2 and CCM3 were 45.45%, 21.21% and 9.09%, respectively. Furthermore, 53.13% of patients were asymptomatic, 17.19% were intracranial haemorrhage and 9.38% were epilepsy. The mean age of symptom onset analysed by KM was 46.67 (40.56-52.78) years.

Conclusion: Based on MRI and genetic analysis, the prevalence of CCMs in the FDRs of families with FCCMs in China was 36.5%. Genetic counselling and MRI screening are recommended for FDRs in patients with more than three CCM lesions on T2WI.

Keywords: Genetics.

Figure 1. Study design and screening process for FDRs of patients with FCCMs. (A) Study design and workflow. (B) FCCM families and FDRs were identified and screened. The dotted box on the left demonstrates the 43 multiple CCM probands for identifying FCCM families by the integration of cranial MRI and WES. The dotted box on the right demonstrates the process of diagnosing CCM by cranial MRI combined with WES in 110 FDRs of multiple CCM probands. FCCMs, familial cerebral cavernous malformations; FDRs, first-degree relatives; CRF, case report form; WES, whole-exome sequencing.

Figure 2. ROC curve for distinguishing patients with FCCMs patients from those with multiple sporadic CCMs by number of the lesions T2WI. The AUC was 0.923 (0.836, 1.000), and the cut-off value based on the maximum Youden index was 3. The sensitivity was 87.10%, and the specificity was 87.50%. AUC, area under the curve; FCCMs, familial cerebral cavernous malformations; ROC, receiver operating characteristic; T2WI, T2-weighted imaging.

Figure 3. The distribution and types of CCM mutations in families with FCCMs. (A) Distribution of CCM mutations among 33 families with FCCMs. (B) Mutation types of the three classical CCM genes. FCCMs, familial cerebral cavernous malformations.

Figure 4. Initial symptoms in patients with FCCMs (n=64). (A) Distribution of initial symptoms in patients with FCCMs. (B) Occurrence of ICH and epilepsy in patients with FCCMs. (C) Cumulative incidence of symptoms in patients in FCCMs. Blue lines represent the cumulative incidence of initial symptoms, red lines represent the cumulative incidence of ICH and green lines represent the cumulative incidence of seizures. (D) Cumulative incidence of FCCM patients with different gene mutations. FCCMs, familial cerebral cavernous malformations; ICH, intracranial haemorrhage.