Department of Medical Genetics, Hôpital de l'Archet 2, CHU de Nice, Nice, France.
Department of Neurology, Gui de Chauliac Montpellier University Hospital, Montpellier University, Montpellier, France.
Eur J Hum Genet. 2024 Jul;32(7):876-878. doi: 10.1038/s41431-024-01626-7. Epub 2024 May 16.
Loss-of-function variants in CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 genes are identified in the vast majority of familial cases with multiple cerebral cavernous malformations. However, genomic DNA sequencing combined with large rearrangement screening fails to detect a pathogenic variant in 5% of the patients. We report a family with two affected members harboring multiple CCM lesions, one with severe hemorrhages and one asymptomatic. No causative variant was detected using DNA sequencing of the three CCM genes, CNV detection analysis, and RNA sequencing. However, a loss of heterozygosity in CCM2 was observed on cDNA sequences in one of the two affected members, which strongly suggested that this locus might be involved. Whole genome sequencing (WGS) identified a balanced structural variant on chromosome 7 with a breakpoint interrupting the CCM2 gene, preventing normal mRNA synthesis. These data underline the importance of WGS in undiagnosed patients with typical multiple CCM.
在绝大多数家族性多发颅内海绵状血管畸形病例中，均可发现 CCM1/KRIT1、CCM2/MGC4607 和 CCM3/PDCD10 基因的功能丧失变异。然而，对基因组 DNA 进行测序并结合大片段重排筛查，仍有 5%的患者无法检测到致病性变异。我们报道了一个家系，有两名受累成员，均存在多发性 CCM 病变，其中一名有严重出血，另一名无症状。对三个 CCM 基因进行 DNA 测序、CNV 检测分析和 RNA 测序均未发现致病变异。然而，在其中一名受累成员的 cDNA 序列中观察到 CCM2 的杂合性丢失，这强烈提示该基因座可能涉及其中。全基因组测序 (WGS) 在 7 号染色体上发现了一个平衡的结构变异，其断点打断了 CCM2 基因，阻止了正常的 mRNA 合成。这些数据强调了 WGS 在典型多发性 CCM 未确诊患者中的重要性。
