Novel Pathogenic Variants in a Cassette Exon of CCM2 in Patients With Cerebral Cavernous Malformations
Autosomal dominant cerebral cavernous malformation (CCM) represents a genetic disorder with a high mutation detection rate given that stringent inclusion criteria are used and copy number variation analyses are part of the diagnostic workflow. Pathogenic variants in either CCM1 (KRIT1), CCM2 or CCM3...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-11-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fneur.2019.01219/full |
| _version_ | 1818009031206240256 |
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| author | Christiane D. Much Konrad Schwefel Dariush Skowronek Loay Shoubash Felix von Podewils Miriam Elbracht Stefanie Spiegler Ingo Kurth Agnes Flöel Henry W. S. Schroeder Ute Felbor Matthias Rath |
| author_facet | Christiane D. Much Konrad Schwefel Dariush Skowronek Loay Shoubash Felix von Podewils Miriam Elbracht Stefanie Spiegler Ingo Kurth Agnes Flöel Henry W. S. Schroeder Ute Felbor Matthias Rath |
| author_sort | Christiane D. Much |
| collection | DOAJ |
| description | Autosomal dominant cerebral cavernous malformation (CCM) represents a genetic disorder with a high mutation detection rate given that stringent inclusion criteria are used and copy number variation analyses are part of the diagnostic workflow. Pathogenic variants in either CCM1 (KRIT1), CCM2 or CCM3 (PDCD10) can be identified in 87–98% of CCM families with at least two affected individuals. However, the interpretation of novel sequence variants in the 5′-region of CCM2 remains challenging as there are various alternatively spliced transcripts and different transcription start sites. Comprehensive genetic and clinical data of CCM2 patients with variants in cassette exons that are either skipped or included into alternative CCM2 transcripts in the splicing process can significantly facilitate clinical variant interpretation. We here report novel pathogenic CCM2 variants in exon 3 and the adjacent donor splice site, describe the natural history of CCM disease in mutation carriers and provide further evidence for the classification of the amino acids encoded by the nucleotides of this cassette exon as a critical region within CCM2. Finally, we illustrate the advantage of a combined single nucleotide and copy number variation detection approach in NGS-based CCM1/CCM2/CCM3 gene panel analyses which can significantly reduce diagnostic turnaround time. |
| first_indexed | 2024-04-14T05:36:52Z |
| format | Article |
| id | doaj.art-aa2a460795ba46208c7cdfca7b23fa83 |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-04-14T05:36:52Z |
| publishDate | 2019-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-aa2a460795ba46208c7cdfca7b23fa832022-12-22T02:09:36ZengFrontiers Media S.A.Frontiers in Neurology1664-22952019-11-011010.3389/fneur.2019.01219475739Novel Pathogenic Variants in a Cassette Exon of CCM2 in Patients With Cerebral Cavernous MalformationsChristiane D. Much0Konrad Schwefel1Dariush Skowronek2Loay Shoubash3Felix von Podewils4Miriam Elbracht5Stefanie Spiegler6Ingo Kurth7Agnes Flöel8Henry W. S. Schroeder9Ute Felbor10Matthias Rath11Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, GermanyDepartment of Human Genetics, University Medicine Greifswald and Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, GermanyDepartment of Human Genetics, University Medicine Greifswald and Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, GermanyDepartment of Neurosurgery, University Medicine Greifswald, Greifswald, GermanyDepartment of Neurology, University Medicine Greifswald, Greifswald, GermanyInstitute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, GermanyDepartment of Human Genetics, University Medicine Greifswald and Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, GermanyInstitute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, GermanyDepartment of Neurology, University Medicine Greifswald, Greifswald, GermanyDepartment of Neurosurgery, University Medicine Greifswald, Greifswald, GermanyDepartment of Human Genetics, University Medicine Greifswald and Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, GermanyDepartment of Human Genetics, University Medicine Greifswald and Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, GermanyAutosomal dominant cerebral cavernous malformation (CCM) represents a genetic disorder with a high mutation detection rate given that stringent inclusion criteria are used and copy number variation analyses are part of the diagnostic workflow. Pathogenic variants in either CCM1 (KRIT1), CCM2 or CCM3 (PDCD10) can be identified in 87–98% of CCM families with at least two affected individuals. However, the interpretation of novel sequence variants in the 5′-region of CCM2 remains challenging as there are various alternatively spliced transcripts and different transcription start sites. Comprehensive genetic and clinical data of CCM2 patients with variants in cassette exons that are either skipped or included into alternative CCM2 transcripts in the splicing process can significantly facilitate clinical variant interpretation. We here report novel pathogenic CCM2 variants in exon 3 and the adjacent donor splice site, describe the natural history of CCM disease in mutation carriers and provide further evidence for the classification of the amino acids encoded by the nucleotides of this cassette exon as a critical region within CCM2. Finally, we illustrate the advantage of a combined single nucleotide and copy number variation detection approach in NGS-based CCM1/CCM2/CCM3 gene panel analyses which can significantly reduce diagnostic turnaround time.https://www.frontiersin.org/article/10.3389/fneur.2019.01219/fullcerebral cavernous malformationsnovel CCM2 mutationsCCM2 transcript analysesCNV analysesseizurescerebral hemorrhage |
| spellingShingle | Christiane D. Much Konrad Schwefel Dariush Skowronek Loay Shoubash Felix von Podewils Miriam Elbracht Stefanie Spiegler Ingo Kurth Agnes Flöel Henry W. S. Schroeder Ute Felbor Matthias Rath Novel Pathogenic Variants in a Cassette Exon of CCM2 in Patients With Cerebral Cavernous Malformations Frontiers in Neurology cerebral cavernous malformations novel CCM2 mutations CCM2 transcript analyses CNV analyses seizures cerebral hemorrhage |
| title | Novel Pathogenic Variants in a Cassette Exon of CCM2 in Patients With Cerebral Cavernous Malformations |
| title_full | Novel Pathogenic Variants in a Cassette Exon of CCM2 in Patients With Cerebral Cavernous Malformations |
| title_fullStr | Novel Pathogenic Variants in a Cassette Exon of CCM2 in Patients With Cerebral Cavernous Malformations |
| title_full_unstemmed | Novel Pathogenic Variants in a Cassette Exon of CCM2 in Patients With Cerebral Cavernous Malformations |
| title_short | Novel Pathogenic Variants in a Cassette Exon of CCM2 in Patients With Cerebral Cavernous Malformations |
| title_sort | novel pathogenic variants in a cassette exon of ccm2 in patients with cerebral cavernous malformations |
| topic | cerebral cavernous malformations novel CCM2 mutations CCM2 transcript analyses CNV analyses seizures cerebral hemorrhage |
| url | https://www.frontiersin.org/article/10.3389/fneur.2019.01219/full |
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