High-throughput sequencing of the entire genomic regions of CCM1/KRIT1 , CCM2 and CCM3/PDCD10 to search for pathogenic deep-intronic splice mutations in cerebral cavernous malformations

Rath, Matthias; Jenssen, Sönke E.; Schwefel, Konrad; Spiegler, Stefanie; Kleimeier, Dana; Sperling, Christian; Kaderali, Lars; Felbor, Ute

doi:10.1016/j.ejmg.2017.06.007

Cited by 13 publications

(6 citation statements)

References 51 publications

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“…However, there are still patients suffering from CCM with normal CCM1 , CCM2 , and CCM3 genetic screen results. Even utilizing next-generation sequencing to screen the whole genome of CCM patients with known and unknown mutations, no causative mutation among all three CCM loci was detected for these CCM patients [37] , further suggesting the existence of a potential new CCM locus.…”

Section: Clinical Presentationmentioning

confidence: 99%

Recent advances in cerebral cavernous malformation research

Padarti¹,

Zhang²

2018

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Cerebral cavernous malformations (CCM) are manifested by microvascular lesions characterized by leaky endothelial cells with minimal intervening parenchyma predominantly in the central nervous system predisposed to hemorrhagic stroke, resulting in focal neurological defects. Till date, three proteins are implicated in this condition: CCM1 (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10). These multi-domain proteins form a protein complex via CCM2 that function as a docking site for the CCM signaling complex, which modulates many signaling pathways. Defects in the formation of this signaling complex have been shown to affect a wide range of cellular processes including cell-cell contact stability, vascular angiogenesis, oxidative damage protection and multiple biogenic events. In this review we provide an update on recent advances in structure and function of these CCM proteins, especially focusing on the signaling cascades involved in CCM pathogenesis and the resultant CCM cellular phenotypes in the past decade.

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Section: Clinical Presentationmentioning

confidence: 99%

Recent advances in cerebral cavernous malformation research

Padarti¹,

Zhang²

2018

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“…Our previous calculations regarding the mutation detection rate included one case that remained unsolved after conventional diagnostic analyses as well as NGS of the entire genomic CCM1-3 regions [Stahl et al, 2008;Spiegler et al, 2014;Rath et al, 2017]. Whole exome sequencing and whole genome sequencing using filter strategies for autosomal dominant and recessive inheritance as well as de novo mutations in a triobased approach (unpublished data) did not reveal a genetic cause for her disease either.…”

Section: Cerebral Cavernous Malformationsmentioning

confidence: 99%

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

et al. 2018

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Based on the latest gnomAD dataset, the prevalence of symptomatic hereditary cerebral cavernous malformations (CCMs) prone to cause epileptic seizures and stroke-like symptoms was re-evaluated in this review and calculated to be 1:5,400-1:6,200. Furthermore, state-of-the-art molecular genetic analyses of the known CCM loci are described which reach an almost 100% mutation detection rate for familial CCMs if whole genome sequencing is performed for seemingly mutation-negative families. An update on the spectrum of CCM1, CCM2, and CCM3 mutations demonstrates that deep-intronic mutations and submicroscopic copy-number neutral genomic rearrangements are rare. Finally, this review points to current guidelines on genetic counselling, neuroimaging, medical as well as neurosurgical treatment and highlights the formation of active patient organizations in various countries.

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“…Thus, genetic screening of all three CCM genes is recommended. However, in these cases, the mutation detection rate is close to 60%, a value much lower than in familial cases [13,78] . The patient should be informed that, even in the presence of a negative test, a genetic cause cannot be ruled out.…”

Section: Genetic Counselingmentioning

confidence: 69%

Molecular genetic analysis of cerebral cavernous malformations: an update

Ricci¹,

Riolo²,

Battistini³

2021

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Cerebral cavernous malformations (CCM) can occur either as sporadic or familial form with autosomal dominant inheritance. Three CCM genes have been identified: CCM1 (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10). In this review, we provide an overall update on genetics of cerebral cavernous malformations. We discuss the main features of these three genes and provide an updated listing of the mutations identified so far. Most of them lead to a premature stop codon regardless of the nature of the variation, including nonsense mutations, small deletions/insertions, and intronic/exonic substitutions causing an altered splicing and a frame-shift. In addition, deletions or duplications of one or more exons of CCM genes can be responsible for the disease. We examine the use of different mutation screening methods to identify all these mutations, providing a comprehensive approach to CCM genetic diagnosis. We also report the main strategies to evaluate the actual impact of the mutations on the protein function. Moreover, we recapitulate the available data on penetrance, phenotype-genotype correlations, and founder effect. Finally, we discuss the main aspects of genetic counseling, including genetic risk assessment in family members, in sporadic patients with multiple CCMs, and in the case of de novo mutations.

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High-throughput sequencing of the entire genomic regions of CCM1/KRIT1 , CCM2 and CCM3/PDCD10 to search for pathogenic deep-intronic splice mutations in cerebral cavernous malformations

Cited by 13 publications

References 51 publications

Recent advances in cerebral cavernous malformation research

Recent advances in cerebral cavernous malformation research

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

Molecular genetic analysis of cerebral cavernous malformations: an update

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