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

Spiegler, Stefanie; Rath, Matthias; Paperlein, Christin; Felbor, Ute

doi:10.1159/000486292

Cited by 73 publications

(71 citation statements)

References 58 publications

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“…In this study, we have identified the first interchromosomal insertion, sometimes also referred to as interchromosomal insertional translocation (IT), in a CCM patient. Notably, current genetic analysis cannot clarify the molecular basis of CCM disease in 2 to 13% of familial cases and up to 40% of sporadic CCM patients 1 . Besides phenocopies, somatic mosaicism and pathogenic variants in an unknown CCM4 gene or non-coding regions of CCM1, CCM2 or CCM3 have been discussed as possible explanations for these patients [21][22][23] .…”

Section: Discussionmentioning

confidence: 99%

First interchromosomal insertion in a patient with cerebral and spinal cavernous malformations

Pilz

Schwefel

Weise

et al. 2020

Sci Rep

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Autosomal dominant cerebral cavernous malformations (ccM) are leaky vascular lesions that can cause epileptic seizures and stroke-like symptoms. Germline mutations in either CCM1, CCM2 or CCM3 are found in the majority of patients with multiple CCMs or a positive family history. Recently, the first copy number neutral inversion in CCM2 has been identified by whole genome sequencing in an apparently mutation-negative CCM family. We here asked the question whether further structural genomic rearrangements can be detected within nGS gene panel data of unsolved ccM cases. Hybrid capture nGS data of eight index patients without a pathogenic single nucleotide, indel or copy number variant were analyzed using two bioinformatics pipelines. In a 58-year-old male with multiple CCMs in his brain and spinal cord, we identified a 294 kb insertion within the coding sequence of CCM2. fine mapping of the breakpoints, molecular cytogenetic studies, and multiplex ligation-dependent probe amplification verified that the structural variation was an inverted unbalanced insertion that originated from 1p12-p11.2. As this rearrangement disrupts exon 6 of CCM2 on 7p13, it was classified as pathogenic. Our study demonstrates that efforts to detect structural variations in known disease genes increase the diagnostic sensitivity of genetic analyses for well-defined Mendelian disorders. Cerebral cavernous malformations (CCM; MIM: 116860, 603284, 603285) are irregular clusters of enlarged and thin-walled vessels that can present as sporadic or autosomal dominant cerebrovascular disease. Aside from epileptic seizures and headaches, CCM patients may present with stroke-like symptoms due to chronic or acute bleeding events 1. Pathogenic germline variants have been identified in CCM1 (also known as KRIT1) 2,3 , CCM2 4,5 , and CCM3 (PDCD10) 6. The mutational spectrum primarily includes nonsense, frameshift, splice, and copy number variants (CNVs). 282 unique CCM1, 84 CCM2 and 75 CCM3 variants are classified as disease-causing in the Human Gene Mutation Database (HGMD Professional 2019.3) 7. Depending on the inclusion criteria for genetic analyses, mutation detection rates of 87 to 98% have been reported for familial CCM cases and up to 60% for sporadic ones 8-11. The mutation detection rate in the latter group could even be higher if patients with associated developmental venous anomalies or a history of radiotherapy to the brain were excluded 1,12. Although pathogenic variants in a yet unknown CCM4 candidate gene have been discussed for unresolved cases 13 , we recently were able to identify the first copy number neutral inversion in CCM2 in an apparently mutation-negative CCM family by whole genome sequencing (WGS) 14. Disease-causing structural variants (SVs) may explain a part of the "missing heritability" in rare diseases 15. SVs are defined as structural and quantitative chromosomal rearrangements that compromise cytogenetically visible and submicroscopic variants 16,17. They contribute to phenotypic variation but can also cause human diseas...

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Section: Discussionmentioning

confidence: 99%

First interchromosomal insertion in a patient with cerebral and spinal cavernous malformations

Pilz

Schwefel

Weise

et al. 2020

Sci Rep

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“…Recently, somatic mutations in GNAQ were identified as a cause of nearly 80% to 90% of Sturge‐Weber cases . Cerebral cavernous malformations (CCMs) are another vascular anomaly that can predispose to focal epilepsy, strokes, and other neurological deficits . Symptomatic individuals with the dominant‐acting mutations in KRIT1 , CCM2 , or PCDC10 have a 40% to 70% chance of experiencing seizures .…”

Section: Focal Epilepsy Syndromesmentioning

confidence: 99%

“…100,101 Cerebral cavernous malformations (CCMs) are another vascular anomaly that can predispose to focal epilepsy, strokes, and other neurological deficits. 102 Symptomatic individuals with the dominant-acting mutations in KRIT1, CCM2, or PCDC10 have a 40% to 70% chance of experiencing seizures. 103 Interestingly, a recent study shows that signaling of the toll-like receptor pathway 4 (TLR4) by gram negative bacteria can act to increase the risk of CCMs and further, the use of antibiotics can prevent the formation of CCMs in a mouse model.…”

Section: Focal Epilepsy Due To Vascular Anomaliesmentioning

confidence: 99%

Epilepsy genetics: Current knowledge, applications, and future directions

2018

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The rapid pace of disease gene discovery has resulted in tremendous advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, and genomes are now available and have led to higher diagnostic rates and insights into the underlying disease processes. As such, the contribution to the care of patients by medical geneticists, neurogeneticists and genetic counselors are significant; the dysmorphic examination, the necessary pre- and post-test counseling, the selection of the appropriate next-generation sequencing-based test(s), and the interpretation of sequencing results require a care provider to have a comprehensive working knowledge of the strengths and limitations of the available testing technologies. As the underlying mechanisms of the encephalopathies and epilepsies are better understood, there may be opportunities for the development of novel therapies based on an individual's own specific genotype. Drug screening with in vitro and in vivo models of epilepsy can potentially facilitate new treatment strategies. The future of epilepsy genetics will also probably include other-omic approaches such as transcriptomes, metabolomes, and the expanded use of whole genome sequencing to further improve our understanding of epilepsy and provide better care for those with the disease.

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“…Due to disorganized tight and adherens junctions between the lining endothelial cells (ECs), CCMs tend to leak into the neighboring brain tissue. Such intracranial hemorrhages from CCMs can lead to focal neurological deficits, epileptic seizures, and recurrent headaches (Draheim, Fisher, Boggon, & Calderwood, 2014;Spiegler, Rath, Paperlein, & Felbor, 2018). A hereditary etiology has first been assumed by H. Kufs in 1928 who described CCMs in a father-daughter duo (Kufs, 1928).…”

Section: Introductionmentioning

confidence: 99%

Precise CCM1 gene correction and inactivation in patient‐derived endothelial cells: Modeling Knudson's two‐hit hypothesis in vitro

Spiegler

Rath

Much

et al. 2019

Molec Gen & Gen Med

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Background The CRISPR/Cas9 system has opened new perspectives to study the molecular basis of cerebral cavernous malformations (CCMs) in personalized disease models. However, precise genome editing in endothelial and other hard‐to‐transfect cells remains challenging. Methods In a proof‐of‐principle study, we first isolated blood outgrowth endothelial cells (BOECs) from a CCM1 mutation carrier with multiple CCMs. In a CRISPR/Cas9 gene correction approach, a high‐fidelity Cas9 variant was then transfected into patient‐derived BOECs using a ribonucleoprotein complex and a single‐strand DNA oligonucleotide. In addition, patient‐specific CCM1 knockout clones were expanded after CRISPR/Cas9 gene inactivation. Results Deep sequencing demonstrated correction of the mutant allele in nearly 33% of all cells whereas no CRISPR/Cas9‐induced mutations in predicted off‐target loci were identified. Corrected BOECs could be cultured in cell mixtures but demonstrated impaired clonal survival. In contrast, CCM1 ‐deficient BOECs displayed increased resistance to stress‐induced apoptotic cell death and could be clonally expanded to high passages. When cultured together, CCM1 ‐deficient BOECs largely replaced corrected as well as heterozygous BOECs. Conclusion We here demonstrate that a non‐viral CRISPR/Cas9 approach can not only be used for gene knockout but also for precise gene correction in hard‐to‐transfect endothelial cells (ECs). Comparing patient‐derived isogenic CCM1 +/+ , CCM1 +/− , and CCM1 −/− ECs, we show that the inactivation of the second allele results in clonal evolution of ECs lacking CCM1 which likely reflects the initiation phase of CCM genesis.

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

Cited by 73 publications

References 58 publications

First interchromosomal insertion in a patient with cerebral and spinal cavernous malformations

First interchromosomal insertion in a patient with cerebral and spinal cavernous malformations

Epilepsy genetics: Current knowledge, applications, and future directions

Precise CCM1 gene correction and inactivation in patient‐derived endothelial cells: Modeling Knudson's two‐hit hypothesis in vitro

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