Next-Generation Sequencing Advances the Genetic Diagnosis of Cerebral Cavernous Malformation (CCM)
Cerebral Cavernous Malformation (CCM) is a cerebrovascular disease of genetic origin that predisposes to seizures, focal neurological deficits and fatal intracerebral hemorrhage. It may occur sporadically or in familial forms, segregating as an autosomal dominant condition with incomplete penetrance...
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MDPI AG
2022-06-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/7/1294 |
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| author | Valerio Benedetti Rosalia Canzoneri Andrea Perrelli Carlo Arduino Andrea Zonta Alfredo Brusco Saverio Francesco Retta |
| author_facet | Valerio Benedetti Rosalia Canzoneri Andrea Perrelli Carlo Arduino Andrea Zonta Alfredo Brusco Saverio Francesco Retta |
| author_sort | Valerio Benedetti |
| collection | DOAJ |
| description | Cerebral Cavernous Malformation (CCM) is a cerebrovascular disease of genetic origin that predisposes to seizures, focal neurological deficits and fatal intracerebral hemorrhage. It may occur sporadically or in familial forms, segregating as an autosomal dominant condition with incomplete penetrance and highly variable expressivity. Its pathogenesis has been associated with loss-of-function mutations in three genes, namely <i>KRIT1</i> (<i>CCM1</i>), <i>CCM2</i> and <i>PDCD10</i> (<i>CCM3</i>), which are implicated in defense mechanisms against oxidative stress and inflammation. Herein, we screened 21 Italian CCM cases using clinical exome sequencing and found six cases (~29%) with pathogenic variants in CCM genes, including a large 145–256 kb genomic deletion spanning the <i>KRIT1</i> gene and flanking regions, and the <i>KRIT1</i> c.1664C>T variant, which we demonstrated to activate a donor splice site in exon 16. The segregation of this cryptic splicing mutation was studied in a large Italian family (five affected and seven unaffected cases), and showed a largely heterogeneous clinical presentation, suggesting the implication of genetic modifiers. Moreover, by analyzing ad hoc gene panels, including a virtual panel of 23 cerebrovascular disease-related genes (Cerebro panel), we found two variants in <i>NOTCH3</i> and <i>PTEN</i> genes, which could contribute to the abnormal oxidative stress and inflammatory responses to date implicated in CCM disease pathogenesis. |
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| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T10:23:32Z |
| publishDate | 2022-06-01 |
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| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-cbc9629f1f084e8abaf5e566f16677842023-12-01T21:49:42ZengMDPI AGAntioxidants2076-39212022-06-01117129410.3390/antiox11071294Next-Generation Sequencing Advances the Genetic Diagnosis of Cerebral Cavernous Malformation (CCM)Valerio Benedetti0Rosalia Canzoneri1Andrea Perrelli2Carlo Arduino3Andrea Zonta4Alfredo Brusco5Saverio Francesco Retta6Department of Clinical and Biological Sciences, School of Medicine and Surgery, University of Torino, Regione Gonzole 10, Orbassano, 10043 Turin, ItalyDepartment of Clinical and Biological Sciences, School of Medicine and Surgery, University of Torino, Regione Gonzole 10, Orbassano, 10043 Turin, ItalyDepartment of Clinical and Biological Sciences, School of Medicine and Surgery, University of Torino, Regione Gonzole 10, Orbassano, 10043 Turin, ItalyCCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, ItalyMedical Genetics Unit, Città della Salute e della Scienza University Hospital, 10126 Turin, ItalyCCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, ItalyDepartment of Clinical and Biological Sciences, School of Medicine and Surgery, University of Torino, Regione Gonzole 10, Orbassano, 10043 Turin, ItalyCerebral Cavernous Malformation (CCM) is a cerebrovascular disease of genetic origin that predisposes to seizures, focal neurological deficits and fatal intracerebral hemorrhage. It may occur sporadically or in familial forms, segregating as an autosomal dominant condition with incomplete penetrance and highly variable expressivity. Its pathogenesis has been associated with loss-of-function mutations in three genes, namely <i>KRIT1</i> (<i>CCM1</i>), <i>CCM2</i> and <i>PDCD10</i> (<i>CCM3</i>), which are implicated in defense mechanisms against oxidative stress and inflammation. Herein, we screened 21 Italian CCM cases using clinical exome sequencing and found six cases (~29%) with pathogenic variants in CCM genes, including a large 145–256 kb genomic deletion spanning the <i>KRIT1</i> gene and flanking regions, and the <i>KRIT1</i> c.1664C>T variant, which we demonstrated to activate a donor splice site in exon 16. The segregation of this cryptic splicing mutation was studied in a large Italian family (five affected and seven unaffected cases), and showed a largely heterogeneous clinical presentation, suggesting the implication of genetic modifiers. Moreover, by analyzing ad hoc gene panels, including a virtual panel of 23 cerebrovascular disease-related genes (Cerebro panel), we found two variants in <i>NOTCH3</i> and <i>PTEN</i> genes, which could contribute to the abnormal oxidative stress and inflammatory responses to date implicated in CCM disease pathogenesis.https://www.mdpi.com/2076-3921/11/7/1294cerebrovascular diseasecerebral cavernous malformation (CCM)next-generation sequencing (NGS)clinical exome sequencing (CES)<i>KRIT1</i>/<i>CCM1</i>aberrant splicing |
| spellingShingle | Valerio Benedetti Rosalia Canzoneri Andrea Perrelli Carlo Arduino Andrea Zonta Alfredo Brusco Saverio Francesco Retta Next-Generation Sequencing Advances the Genetic Diagnosis of Cerebral Cavernous Malformation (CCM) Antioxidants cerebrovascular disease cerebral cavernous malformation (CCM) next-generation sequencing (NGS) clinical exome sequencing (CES) <i>KRIT1</i>/<i>CCM1</i> aberrant splicing |
| title | Next-Generation Sequencing Advances the Genetic Diagnosis of Cerebral Cavernous Malformation (CCM) |
| title_full | Next-Generation Sequencing Advances the Genetic Diagnosis of Cerebral Cavernous Malformation (CCM) |
| title_fullStr | Next-Generation Sequencing Advances the Genetic Diagnosis of Cerebral Cavernous Malformation (CCM) |
| title_full_unstemmed | Next-Generation Sequencing Advances the Genetic Diagnosis of Cerebral Cavernous Malformation (CCM) |
| title_short | Next-Generation Sequencing Advances the Genetic Diagnosis of Cerebral Cavernous Malformation (CCM) |
| title_sort | next generation sequencing advances the genetic diagnosis of cerebral cavernous malformation ccm |
| topic | cerebrovascular disease cerebral cavernous malformation (CCM) next-generation sequencing (NGS) clinical exome sequencing (CES) <i>KRIT1</i>/<i>CCM1</i> aberrant splicing |
| url | https://www.mdpi.com/2076-3921/11/7/1294 |
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