Variable expression of cerebral cavernous malformations in carriers of a premature termination codon in exon 17 of the Krit1 gene

Abstract

BackgroundCerebral cavernous malformations (CCM) present as either sporadic or autosomal dominant conditions with incomplete penetrance of symptoms. Differences in genetic and environmental factors might be minimized among first-degree relatives. We therefore studied clinical expression in a family with several affected members.MethodsWe studied a three-generation family with the onset of CCM as a cerebral haemorrhage in the younger (four-year-old) sibling. Identification and enumeration of CCMs were performed in T2-weighted or gradient-echo MRIs of the whole brains. Genetic analysis comprised SCCP, sequencing and restriction polymorphism of the Krit1 gene in the proband and at risk relatives.ResultsThe phenotypes of cerebral cavernous malformations (CCMs) in carriers of Krit1 mutations were very variable. We identified a novel frameshift mutation caused by a 1902A insertion in exon 17 of the Krit1 gene, which leads to a premature TAA triplet and predicts the truncating phenotype Y634X. A very striking finding was the absence of both clinical symptoms and CCMs in the eldest sibling harbouring the 1902insA.ConclusionsPatients in this family, harbouring the same mutation, illustrate the very variable clinical and radiological expression of a Krit1 mutation. The early and critical onset in the proband contrasts with minor clinical findings in affected relatives. This consideration is important in genetic counselling.

Endothelial Cilia Are Essential for Developmental Vascular Integrity in Zebrafish

“…Interestingly, similar variable penetrance of ICH has been described in both zebrafish and human. 28,[50][51][52] In contrast to mouse strains, zebrafish lines are generally of very mixed genetic background. 53 Clearly, there are additional risk factors that remain to be identified.…”

Cerebral Cavernous Malformations: An Update on Prevalence, Molecular Genetic Analyses, and Genetic Counselling

“…Future studies with high-sensitivity techniques are necessary to address this open question in larger CCM cohorts. As mentioned above, the course of the disease can vary significantly between individuals that share the same germline mutation even within a single CCM family [Lucas et al, 2003;Spiegler et al, 2014;Fauth et al, 2015]. Given that a second somatic mutation cannot be identified in all cases, it is reasonable to hypothesize that yet to be identified regulatory mechanisms and different expression levels of modifier genes may also trigger disease onset and contribute to incomplete disease penetrance and variable expressivity of CCM.…”

Combinatorial interaction between CCM pathway genes precipitates hemorrhagic stroke

“… Intracerebral hemorrhage (ICH) is a particularly severe form of stroke whose etiology remains poorly understood, with a highly variable appearance and onset of the disease (Felbor et al, 2006; Frizzell, 2005; Lucas et al, 2003). In humans, mutations in any one of three “CCM” genes causes an autosomal dominant genetic ICH disorder characterized by C erebral C avernous M alformations.…”